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Clinical Insights: February 2019

Friday, February 22, 2019

Release Date: February 22, 2019
Expiration Date: February 22, 2020


This activity is provided free of charge.

STATEMENT OF NEED

This CE article is designed to serve as an update on cancer detection and prevention and to facilitate clinical awareness of current and new research regarding state-of-the-art care for those with or at risk for cancer.

TARGET AUDIENCE

Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may participate in this CE activity.
 
EDUCATIONAL OBJECTIVES

Upon completion, participants should be able to:
  • Describe new preventive options and treatments for patients with cancer
  • Identify options for individualizing the treatment for patients with cancer
  • Assess new evidence to facilitate survivorship and supportive care for patients with cancer
ACCREDITATION/CREDIT DESIGNATION STATEMENT

Physicians’ Education Resource®, LLC is approved by the California Board of Registered Nursing, Provider #16669 for 1 Contact Hour.
 
DISCLOSURES/RESOLUTION OF COI

It is the policy of Physicians’ Education Resource®, LLC (PER®) to ensure the fair balance, independence, objectivity, and scientific objectivity in all of our CE activities. Everyone who is in a position to control the content of an educational activity is required to disclose all relevant financial relationships with any commercial interest as part of the activity planning process. PER® has implemented mechanisms to identify and resolve all conflicts of interest prior to release of this activity.The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial interests pertaining to this activity.

METHOD OF PARTICIPATION
  1. Read the articles in this section in its entirety.
  2. Go to www.gotoper.com/go/ONN18September
  3. Complete and submit the CE posttest and activity evaluation.
  4. Print your CE Certificate.
OFF-LABEL DISCLOSURE/DISCLAIMER

This CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CE activity is for continuing medical nursing purposes only and is not meant to substitute for the independent medical judgment of a nurse or other healthcare provider relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual authors and do not reflect those of PER®.

Myelodysplastic Syndrome

Luspatercept Reduces Blood Transfusion Dependence in Lower-Risk MDS Anemia

Kristie L. Kahl

Treatment with luspatercept significantly reduced the need for frequent red blood cell (RBC) transfusions in nearly 53% of patients with anemia associated with low-to intermediate-risk myelodysplastic syndrome (MDS), according to results from the phase III MEDALIST trial presented at the 2018 American Society of Hematology Annual Meeting.

The novel agent was generally well tolerated among patients who required regular RBC transfusions and demonstrated abnormal iron overload in RBC precursors (ring sideroblasts) before participating in the trial, said study investigator Alan F. List, MD, president and chief executive officer of Moffitt Cancer Center, during a press conference.

Luspatercept is a first-in-class erythroid maturation agent that is believed to regulate late-stage RBC maturation. Lower-risk MDS-associated anemia may be associated with ineffective erythropoiesis, which leads to anemia and RBC transfusion dependence, explained List.

Erythropoiesis-stimulating agents (ESAs) are a first-line therapy for patients with anemia associated with lower-risk MDS; however, few treatment options exist for patients who are refractory to, unresponsive to, or ineligible for these agents, List added.

MEDALIST TRIAL DETAILS

The MEDALIST trial evaluated the efficacy and safety of luspatercept compared with placebo in patients 18 years or older who had anemia due to MDS defined as very low, low, or intermediate risk according to the Revised International Prognostic Scoring System. Eligible participants also had ring sideroblasts ≥15% or ≥5% with an SF3B1 mutation, required 2 or more units of blood every 8 weeks, had bone marrow blasts <5%, and were refractory to, intolerant of, or ineligible for ESAs. The study was conducted between March 2016 and June 2017 across 65 international sites.

As of the May 8, 2018, cutoff date, 229 patients with a median age of 71 years (range, 26-95) were randomized 2:1 to receive either luspatercept subcutaneously at a starting dose of 1 mg/kg every 3 weeks, with titration up to 1.75 mg/kg if needed (n = 153) or placebo subcutaneously every 3 weeks (n = 76) for ≥24 weeks.

Investigators assessed for MDS disease after 24 weeks and every 6 months thereafter; treatment was discontinued if there was no clinical benefit or if disease progression occurred. Patients were followed for at least 3 years after their last dose for acute myeloid leukemia progression and subsequent MDS treatment and survival.

Patients were a median 41.8 months (range, 3-421) out from diagnosis, and the majority were men (62.9%). They received a median 5 RBC units (range, 1-20) transfused over 8 weeks during the 16 weeks prior to treatment, including 43.2% who had ≥6 RBC units over 8 weeks, 27.9% who had ≥4 to <6 RBC units over 8 weeks, and 28.8% who had <4 RBC units over 8 weeks.

At baseline, 138 (60.3%) participants had serum erythropoietin levels <200 IU/L, 58 (25.3%) had levels 200 to 500 IU/L, and 32 (14.0%) had levels >500 IU/L. In total, 218 patients (95.2%) had previously received ESAs. Additionally, 206 (90.0%) tested positive for an SF3B1 mutation.

TRIAL RESULTS

In the randomized trial, 52.9% of patients treated with luspatercept achieved a modified hematologic improvement–erythroid response compared with 11.8% of those given placebo (P <.0001). Overall, 37.9% of patients treated with luspatercept experienced RBC transfusion independence for ≥8 weeks, which was the primary endpoint of the study, compared with 13.2% in the placebo arm (odds ratio, 5.1; P <.0001). Additionally, luspatercept improved outcomes for 2 key secondary endpoints.

The safety profile of luspatercept appeared consistent with that reported for the drug in the dose-finding phase II PACE-MDS study2: Three treatment-related grade 3 adverse events occurred in 1 patient each (myalgia, increased blast cell count, and general physical health deterioration)
Multiple Myeloma

Daratumumab Triplet Forms New Frontline Standard in Transplant-Ineligible Myeloma

Jason Broderick

The triplet of daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone (DRd) reduced the risk of disease progression or death by 44% compared with lenalidomide plus dexamethasone (Rd) in patients with newly diagnosed multiple myeloma who were not candidates for high-dose chemotherapy and autologous stem cell transplant (ASCT).

Findings from the phase III MAIA study show that at a median follow-up of 28 months (range, 0.0-41.4), the median progression-free survival (PFS) had not been reached with DRd compared with 31.9 months in the Rd group (hazard ratio, 0.56; 95% CI, 0.43-0.73; P <.0001). The PFS rate at 30 months was 71% versus 56%, respectively.

“These results support DRd as a new standard of care for patients with transplant-ineligible newly diagnosed multiple myeloma,” said lead author Thierry Facon, MD, of Claude Huriez Hospital in Lille, France.

The overall response rate was 93% with DRd compared with 81% with Rd (P <.0001). The stringent complete response rate (30% vs 12%), CR rate (17% vs 12%), and very good partial response rate (32% vs 28%) were all higher with DRd versus Rd. However, the partial response rate was higher in the Rd versus DRd group, at 28% versus 14%, respectively.

Facon also reported that the minimal residual disease–negative rate was “greater than 3-fold higher” with DRd versus Rd, at 24% versus 7%, respectively.

The open-label, multicenter phase III MAIA trial included 737 patients with newly diagnosed multiple myeloma who were not candidates for high-dose chemotherapy and ASCT. Fifty-two percent of the patients were male, and 92% were white. The ECOG performance status was 0-1 for 83% of patients.

The median patient age was 73 years (range, 45-90). Only 1% of patients were older than 65 years, while 44% of patients were 75 years or older. Facon noted that this proportion of patients is much higher than that from any previous trial in this population.

“We see a very strong clinically significant benefit in extending survival without the cancer getting worse, with no major safety concerns,” said Facon. “In older patients who are not candidates for stem cell transplantation, these are very encouraging results.”

Per the multiple myeloma international staging system, 27% of patients were stage I, 43% of patients were stage II, and 29% were stage III. Of the total population, cytogenetic risk level could be determined for 642 patients. Eighty-six percent of these patients were standard risk and 14% were high risk.

Patients were randomized to lenalidomide (25 mg orally on days 1-21 of each 28-day cycle) and dexamethasone with or without daratumumab. Dexamethasone was administered to patients younger than 70 years at 40 mg orally or intravenously (IV) once a week and to those older than 75 with a body mass index <18.5 at 20 mg weekly.

Daratumumab was administered at 16 mg/kg IV weekly for the first 8 weeks (cycles 1 and 2), every other week for 16 weeks (cycles 3-6), and then every 4 weeks (cycle 7 and beyond) until disease progression or unacceptable toxicity. PFS was the primary endpoint.

ADVERSE EVENT PROFILE

The most common grade 3/4 hematologic treatment-emergent adverse events (TEAEs) in the DRd arm were neutropenia (50% vs 35% with Rd), lymphopenia (15% vs 11%, respectively), anemia (12% vs 20%), and thrombocytopenia (7% vs 9%).

The most frequently occurring grade 3/4 nonhematologic TEAEs in the DRd arm included pneumonia (14% vs 8% with Rd); fatigue (8% vs 4%, respectively); diarrhea (7% vs 4%); deep vein thrombosis, pulmonary embolism, or both (6% in each arm); asthenia (4% in each arm); back pain (3% in each arm); constipation (2% vs <1%); peripheral edema (2% vs <1%); and nausea (1% vs <1%).

Frontline daratumumab was previously approved in multiple myeloma for use in combination with bortezomib (Velcade), melphalan, and prednisone (VMP) for the treatment of patients who are ineligible for ASCT. However, the VMP regimen is primarily used in Europe, not in the United States.

Additionally, the ongoing Cassiopeia trial is examining daratumumab in combination with bortezomib, thalidomide, and dexamethasone (VTd) as a frontline treatment for transplant-eligible patients with newly diagnosed multiple myeloma (NCT02541383)

REFERENCES
  1. Facon T, Kumar SK, Plesner T, et al. Phase 3 Randomized Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant (MAIA). Presented at: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, California. Abstract LBA-2.
 
Acute Myeloid Leukemia
Nurse Perspective

Phyllis McKiernan, MSN, APN, OCN 
Blood and Marrow Stem Cell Transplantation Program 
John Theurer Cancer Center, Hackensack, NJPhyllis McKiernan, MSN, APN, OCN
Blood and Marrow Stem Cell Transplantation Program
John Theurer Cancer Center, Hackensack, NJ



For patients with newly diagnosed multiple myeloma, induction therapy using a proteasome inhibitor and/or an immunomodulator, followed by high-dose melphalan with autologous stem cell transplant (ASCT), is a standard therapeutic approach. Results from multiple studies show that ASCT is a feasible option for patients aged 65 to 75 years, so chronologic age should not be the only criteria used to determine eligibility. However, older patients with a high comorbidity score and poor performance status may not be eligible for ASCT due to increased risk of poor outcomes. The number of therapy options for transplant-ineligible patients continues to increase as more novel agents, including monoclonal antibodies, are approved for multiple myeloma. Finding combination therapies that achieve deep responses without adding toxicities is a paramount objective.

These study results show that adding daratumumab (Darzalex) to the established regimen of lenalidomide (Revlimid) and dexamethasone (Rd) produces a superior overall response rate and progression-free survival for transplant-ineligible patients with newly diagnosed disease compared with Rd alone. In addition, more patients who received Rd with daratumumab achieved minimal residual disease (MRD) negativity. Using MRD negativity to further define complete response is a widely accepted goal for patients with high-risk disease, and there are ongoing studies on the use of MRD testing as a basis for making clinical decisions. For transplant-ineligible patients, the next steps following induction, such as maintenance versus observation, need to be established, and using MRD status could be useful.

 

Beat AML Trial Proves Feasibility of Rapid Treatment Assignment Following Diagnosis

Kristie L. Kahl

Hematologists may soon have the ability to determine acute myeloid leukemia (AML) subtype based on genetic analysis of blood samples in 7 days or less, a process that could become an integral part of diagnosing and treating AML in this patient population, according to Amy Burd, PhD.

Initial findings from the Beat AML study show that rapid genetic testing in patients with AML was feasible and helpful and that a precision medicine approach is possible for these patients, who must be treated urgently given the disease’s rapid progression.1

In the study, 273 patients aged 60 or older were identified as candidates for targeted therapy within 7 days of their samples arriving at a reference lab for testing, compared with just 12 who were not.1 “Implementation of a rapid treatment assignment umbrella study in elderly patients with AML is feasible, with [more than] 95% of patients assigned to treatment in less than 7 days,” Burd said.

The multiarm, multisite collaborative trial, led by the Leukemia and Lymphoma Society (LLS), is designed to test targeted therapy approaches for improving the generally poor prognosis among patients with AML. “Acute myeloid leukemia is the most commonly diagnosed leukemia, with 20,000 patients a year and an overall survival of [approximately] 25%,” said Burd, vice president of research strategy at LLS, referring to the 5-year rate. “AML is a heterogenous disease. It is driven by the serial acquisition of mutations that lead to interpatient heterogeneity, in both biology and clinical response,” she added. “...we hypothesized: Could we improve outcomes by matching patients to the appropriate [targeted] therapy?”

In her presentation, Burd, lead study author of the Beat AML study, discussed whether a multicenter clinical trial could use genetic profiling to assign patients to molecularly defined, subtype-specific therapies within 7 days. In addition, the researchers aimed to delineate the potential for new therapies to improve outcomes among older patients with AML in the frontline setting.

OBJECTIVES OF UMBRELLA TRIAL

The ongoing Beat AML trial has 3 primary objectives: to determine the feasibility of completing molecular, immunophenotypic, and/or biochemical studies in 7 or fewer calendar days; to assess the feasibility of assigning patients to substudies according to a master protocol, based on results from the testing; and to evaluate the clinical efficacy of novel treatment strategies in each of the substudies.

To be eligible, patients must have a new diagnosis with no prior AML treatment, other than hydroxyurea, and be aged 60 or older at the time of diagnosis. Burd noted these requirements are in line with FDA recommendations to incorporate broad eligibility criteria to capture the majority of patients with AML. The malignancy is most frequently diagnosed among people aged 65 to 74 years, with a median age at diagnosis of 68 years.2

Out of a total of 285 enrolled patients, many were 75 years or older (n = 108; 37.9%) and male (58.6%). To create a genetic profile for each patient, the researchers applied 3 genetic analysis techniques: cytogenetics, polymerase chain reaction, and next-generation sequencing.

Patients were then considered for therapy using a precision medicine–based stratification algorithm that considered assignment for:

Known responsive attributes, such as core-binding factor AML (CBF-AML) and NPM1 mutation–positive (NPM1+)/FLT3 wild-type AML

Driver cytogenetic aberrations, such as 11q23/ MLL-rearranged AML and TP53 wild-type/ complex karyotype AML

A mutation clone with a variant allele frequency ≥0.3 by next-generation sequencing3

If patients were not assigned to a genomic group during initial stratification, a second run-through of the algorithm was performed, assessing for a mutation clone with VAF ≥0.2.1,3 From highest to lowest, genomic stratification assignments were prioritized by CBF-AML, NPM1+/FLT3 wild-type, 11q23/ MLL-rearranged, IDH2-positive, IDH1-positive, TP53- positive, TP53 wild-type/complex karyotype, FLT3- ITD-positive or FLT3-TKD-positive, WT1-positive or TET2-positive, and marker-negative AML.

BEAT AML UPDATE

The study, which launched on November 16, 2016, has enrolled 356 patients thus far; however, 66 patients were removed from the study because they turned out to not have AML upon laboratory analysis.

Of 285 patients who were identified as candidates for treatment, 146 have gone on to the second phase of the study, where they have been treated in a clinical trial for experimental therapies targeting their AML subtype.

Of those who have not been treated in phase II (n = 139; 48.8%), most chose other therapies, such as standard care (n = 57; 20%), an alternative trial after assignment (n = 26; 9.1%), palliative care (n = 23; 8.1%), or an alternative treatment before clinical assignment (n = 20; 7%). Seven patients (2.5%) died during the 7-day period, and outcomes for 6 participants (2.1%) were considered “not specified” at the time of study analysis.

Burd emphasized that although clinicians offered treatment assignment within 7 days, the ultimate decision was always guided by what was best for the patient, “even if that means a treatment [option] outside of the study,” she added.

In 2016, the study included just 3 experimental treatment arms; today, 11 substudies of therapies developed by 7 pharmaceutical companies are ongoing under the Beat AML umbrella. These include studies into the novel drugs entospletinib, a SYK inhibitor; pevonedistat, a Nedd8 inhibitor; and BI 836858, an anti-CD33 monoclonal antibody. The study also has open arms testing 2 FDA-approved drugs: enasidenib (Idhifa), an IDH2 inhibitor, and gilteritinib (Xospata), a FLT3 inhibitor.

“The majority of patients assigned to protocol therapy proceeded to trial, with an increase in the frequency [of trial assignment] as new protocols opened,” Burd said. “And we’ve seen promising efficacy in several of the treatment arms to date.”

Because of AML’s rapid progression, and the urgency to start treatment as soon as possible, press conference moderator Joseph R. Mikhael, MD, chief medical officer of the International Myeloma Foundation, applauded the efforts of the Beat AML investigators: “One of the greatest challenges we’ve faced in the concept of precision medicine is that, by the time you determine what is best for that patient for diseases like AML and many other hematologic diseases, in a sense, the horse is already out of the barn, meaning you have to have started the patient on treatment already or else their disease could have progressed quite rapidly.

REFERENCES
  1. Burd A, Levine RL, Shoben A, et al. Initial report of the Beat AML umbrella study for previously untreated AML: evidence of feasibility and early success in molecularly driven phase 1 and 2 studies. Presented at: 2018 Annual Meeting; Dec. 1-4, 2018; San Diego. Abstract 559. ash.confex.com/ash/2018/webprogram/Paper118494.html.
  2. SEER Cancer Stat Facts: acute myeloid leukemia. National Cancer Institute website. seer.cancer.gov/statfacts/html/amyl.html. Accessed December 2, 2018
  3. Mahaseth H, Brutcher E, Kauh J, et al. Modified FOLFIRINOX regimen with improved safety and maintained efficacy in pancreatic adenocarcinoma. Pancreas. 2013;42(8):1311-1315. doi: 10.1097/MPA.0b013e31829e2006.
  4. Mims AS, Kohlschmidt J, Borate U, et al. A precision medicine hierarchical classification developed using variant allele frequency (VAF) for treatment of older patients (pts) with acute myeloid leukemia (AML): Alliance Clinical Trials in Oncology (Alliance) historical patient control. Presented at: ASH Annual Meeting; Dec. 1-4, 2018; San Diego. Abstract 1489. ash.confex.com/ash/2018/webprogram/Paper116717.html.
 
Chronic Lymphocytic Leukemia

Liso-Cel Demonstrates Durable Responses in Heavily Pretreated, High-Risk CLL

Gina Columbus Lisocabtagene maraleucel (liso-cel; JCAR017) appeared tolerable and induced an 81.3% best overall response rate (ORR) and 43.8% complete response (CR) or CR with incomplete blood count recovery (CRi) rate in heavily pretreated, high-risk patients with chronic lymphocytic leukemia (CLL) who previously received ibrutinib (Imbruvica), according to the dose-finding results of a small phase I/II trial presented at the 2018 American Society of Hematology Annual Meeting.

The CD19-directed 4-1BB chimeric antigen receptor (CAR) T-cell therapy also showed low rates of grade 3 cytokine release syndrome (CRS) and neurotoxicity, explained lead study author Tanya Siddiqi, MD, an assistant clinical professor in the Department of Hematology and Hematopoietic Cell Transplantation, City of Hope in Duarte, California, in a presentation during the meeting.

Patients who progress on B-cell receptor inhibitors have a poor prognosis, Siddiqi explained, adding that CR and undetectable minimal residual disease (uMRD) rates with this class of agents remain inadequate—creating an unmet need for this patient population.

Liso-cel consists of a defined CD4 and CD8 composition and 4-1BB costimulatory domain; its defined composition allows administration of a precise dose of treatment. In December 2016, the CAR T-cell therapy was granted a breakthrough therapy designation by the FDA for patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, grade 3b follicular lymphoma, or not otherwise specified disease that is de novo or transformed from indolent lymphoma.

The phase I TRANSCEND CLL 004 study (NCT03331198) investigated 16 patients with relapsed/refractory CLL or small lymphocytic lymphoma who failed on or were ineligible to receive a BTK inhibitor. Patients with high-risk disease must have failed on ≥2 prior therapies, while those with standard-risk disease must have progressed on ≥3 prior treatments. Their ECOG performance status was 0 or 1.

The median age was 64.5, and 50% of patients were male. Rai stage III/IV and Binet stage C were both detected in 10 patients. Additionally, high-risk features were reported, including TP53 mutation (n = 10), complex karyotype (n = 8), and 17p deletion (n = 7). All 16 patients received prior ibrutinib, most received the BTK inhibitor in the relapsed/refractory setting (n = 13), and 8 patients had ibrutinib (Imbruvica) progression and prior venetoclax (Venclexta).

The dose-escalation modified toxicity probability-interval-2 trial comprised a 28-day dose-limiting toxicity (DLT) period. The dose levels were –1 (2.5 x 107; n = 0), 1 (5 x 107; n = 6), and 2 (1 x 108; n = 10). Following enrollment and apheresis, liso-cel was manufactured and bridging therapy was allowed. This was followed by lymphodepletion with fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2 for 3 days, then 2 to 7 days later, liso-cel was administered. On-study follow-up was 24 months, with a long-term follow-up planned for up to 15 years after the last liso-cel infusion. The primary endpoint was to determine the recommended dose and safety, while exploratory objectives were antitumor activity and pharmacokinetics.

Grade ≥3 treatment-emergent adverse events (AEs) were reported in all patients; the most frequently reported were thrombocytopenia (75%), anemia (68.8%), neutropenia (62.5%), and leukopenia (56.3%). Grade ≥3 treatment-related AEs were observed in 9 patients (56.3%), the most notable being neutropenia (37.5%), leukopenia (31.3%), lymphopenia (31.3%), and anemia (25.0%). There was 1 DLT of grade 4 hypertension, which was reported in dose level 2.

All serious AEs were grade ≥3 and observed in 7 patients (43.8%): lung infection (18.8%) and aphasia, decreased blood fibrinogen, encephalopathy, febrile neutropenia, hypertension, and hyponatremia in 1 patient each (6.3%).

Overall and grade 3 AEs of special interest were CRS (75% and 6.3%, respectively), neurologic events (37.5% and 18.8%), and tumor lysis syndrome (12.5% and 12.5%). CRS of any grade was more common in the dose level 1 cohort than dose level 2 (100% vs 60%), but neurologic events of any grade occurred at a lower rate (33.3% vs 40.0%). Grade 3 tumor lysis syndrome occurred in 1 patient in each dose level cohort. The percentage of patients who experienced both CRS and neurologic events was comparable in dose levels 1 and 2 (33.3% vs 30.0%).

Response was assessed at 30 days following treatment with liso-cel. Across both cohorts, the ORR was 75% (n = 12), with a 31.3% CR/CRi rate (n = 5) and a 43.8% partial response (PR) or nodular PR (nPR) rate (n = 7). In the dose level 1 cohort, the ORR was still 100%, with a 50% CR/CRi and PR/ nPR rate (n = 3 each). The ORR, CR/CRi rate, and PR/nPR rate were 60% (n = 6), 20% (n = 2), and 40% (n = 4), respectively, in the dose level 2 cohort.

Efficacy was again evaluated at 3 months post treatment with liso-cel. Overall, the ORR was 80% (n = 8), the CR/CRi rate was 50% (n = 5), and the PR/nPR rate was 30% (n = 3). In the dose level 1 cohort, these rates were 83.3% (n = 5), 50% (n = 3), and 33.3% (n = 2), respectively, and in the dose level 2 group, 75% (n = 3), 50% (n = 2), and 25% (n = 1).

Aside from the 81.3% (n = 13) best ORR and 43.8% (n = 7) CR/CRi rate, results showed that the PR/nPR rate was 37.5% (n = 6), the stable disease (SD) rate was 12.5% (n = 2), and there was 1 case of progressive disease (PD; 6.3%).

In the dose level 1 cohort, the ORR was 100%, the CR/CRi rate was 83.3% (n = 5), and the PR/ nPR rate was 16.7% (n = 1). There were no cases of SD or PD. In the dose level 2 cohort, the rates were 70% (n= 7), 20% (n = 2), and 50% (n = 5), respectively; the SD rate was 20% (n = 2), and the PD rate was 10% (n = 1).

Minimal residual disease was evaluated at 10-4 sensitivity via 6-color flow cytometry using peripheral blood and at 10-6 sensitivity by clonoSEQ deep sequencing of bone marrow aspirates. Eleven patients (73.3%) had uMRD sensitivity 10-4 (uMRD4) via flow cytometry at day 30; all continue to remain undetectable at the most recent follow-up, Siddiqi noted. All 5 patients with a postdose follow-up at 6 months continue to maintain uMRD4 response.

The pharmacokinetic/pharmacodynamic profile showed that the median time to peak expansion for all patients was 16 days (range, 4-30). Results of a correlative biomarker analysis, in which 38 cytokines were analyzed in 13 patients within the first 30 days of treatment, showed that interleukin-16 and tumor necrosis factor were elevated before onset in 3 of 4 patients who experienced grade 2/3 neurologic events. REFERENCES
  1. Siddiqi T, Soumerai JD, Wierda WG, et al. Rapid MRD-negative responses in patients with relapsed/refractory CLL treated with liso-cel, a CD19-directed CAR T-cell product: preliminary results from TRANSCEND CLL 004, a phase 1/2 study including patients with high-risk disease previously treated with ibrutinib. Presented at: 2018 ASH Annual Meeting and Exposition; December 1-4, 2018; San Diego. Abstract 300.
 
Acute Lymphoblastic Leukemia

First HCT Following CAR T-Cell Therapy Reduces Risk for ALL Relapse

Kristie L. Kahl

Receiving a stem cell transplant for the first time following CD19 chimeric antigen receptor (CAR) T-cell therapy induced a reduction in the risk for acute lymphoblastic leukemia (ALL) recurrence, according to the results of a retrospective analysis of the phase I/II PLAT-02 study.1

However, those who previously underwent transplantation failed to derive as much leukemia-free survival (LFS) benefit from hematopoietic cell transplant (HCT) after CAR T-cell therapy, leaving the role of the procedure in these patients unclear, according to Corinne Summers, MD, principal investigator of the Ben Towne Center at Seattle Children’s Hospital.

In the phase I/II PLAT-02 study, the researchers aimed to determine the feasibility of manufacturing autologous SCRI-CAR19 product, investigate the safety of cryopreserved CD19 CAR T-cell product infusion, and describe the toxicity profile among 64 pediatric and young adult patients with CD19- positive B-cell ALL. In phase I, the CAR T-cell therapy, across 4 doses (0.5 x 106 CAR T cells/kg [n = 13], 1 x 106 CAR T cells/kg [n = 18], 5 x 106 CAR T cells/kg [n = 7], and 10 x 106 CAR T cells/kg [n = 5]) demonstrated robust responses in 43 patients, with a minimal residual disease–negative complete remission rate of 93% at 21 days following treatment.

In phase II, a minimal change in CAR T-cell manufacturing was introduced with product infusion in 21 patients who were treated with a dose of 1 X 106 CAR T cells/kg, which was associated with longer responses in CAR T-cell persistence.2

The retrospective analysis included follow-up of at least 1 year in 32 patients from the phase I dose-planning portion of the trial and 18 from the initial phase II cohort. Patients who had no response to CAR T-cell therapy (n = 4), relapsed prior to day 63 (n = 9), or had grade 5 dose-limiting toxicity (n = 1) were excluded from the retrospective analysis. Of the 50 evaluable patients, 34 had a history of at least 1 prior HCT compared with 16 who had no history of HCT.

The researchers observed a trend toward improved LFS (P = .01) among patients who underwent HCT following CAR T-cell therapy; however, they found no difference in OS between the 2 groups.

Of the patients without a history of HCT, 13 underwent the procedure after therapy; only 2 experienced relapse. Two of the 3 patients who did not undergo HCT after CAR T-cell therapy relapsed, however, and the third remains in remission after 28 months of follow-up.

Of the patients who previously underwent HCT, 24 did not undergo a second procedure following CAR T-cell therapy, of whom 8 remain in remission; meanwhile, 10 patients had a second procedure, and 5 remain in remission after at least 24 months of follow-up.

Fourteen patients experienced early loss of CD19 CAR T-cell persistence, of whom 8 underwent HCT following therapy. Six of these patients received a second HCT, which also demonstrated LFS benefit, showing a potential role for second HCT following CD19 CAR T-cell therapy, Summers said. By contrast, the 6 patients who did not undergo HCT all relapsed.

Summers concluded further follow-up is needed to determine the role of HCT in patients who have a history of transplant and to evaluate the lack of OS benefit seen between arms.

REFERENCES
  1. Summers C, Annesley C, Bleakley M, et al. Long Term Follow-up after SCRI-CAR19v1 Reveals Late Recurrences As Well As a Survival Advantage to Consolidation with HCT after CAR T Cell Induced Remission. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego. Abstract 967
  2. Ceppi F, Annesley C, Finney O. Minimal Change in CAR T Cell Manufacturing Can Impact in Expansion and Side Effect of the CAR T Cell Therapy. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego. Abstract 4012.
  Nurse Perspective

Kristin E. Barber, FNP-BC, AOCNPKristin E. Barber, FNP-BC, AOCNP
Hematology/ Oncology
Huntsman Cancer Institute



Children and young adults diagnosed with acute lymphoblastic leukemia (ALL) typically go through intense chemotherapy which usually spans the course of 2 to 3 years. Common chemotherapy agents used during the induction period are vincristine (Oncovin), daunorubicin (Cerubidine), pegaspargase (Oncaspar) and prednisone. The initial induction is over 28 days followed by a repeat bone marrow biopsy to see if patients are in remission. After induction, they are treated through consolidation, intensification, and then maintenance chemotherapy. If patients develop relapsed disease while on maintenance, they typically will re-intensify or change chemotherapy and proceed to allogeneic bone marrow transplant. In 2017, chimeric antigen receptor (CAR) T-cell therapy offered a new option for these relapsed patients and is also being used to attempt to prolong remission.

In the PLAT-02 study, Corrine Summer, MD, and colleagues are addressing critical questions about when to offer CAR T cells to patients with ALL and when to time an allogeneic bone marrow transplant in relation to their CAR T-cell treatment.

The patient’s entire healthcare team must learn to recognize toxicities related to CAR T-cell therapy. The 2 most common are cytokine release syndrome and neurotoxicity. At the Huntsman Cancer Hospital in Salt Lake City, Utah, we established a CAR T-cell therapy program in early 2018. Now, almost 1 year into the process, our bone marrow transplant doctors, advanced practitioners, nurses, pharmacists along with our ICU and ER staff are all trained to recognize and intervene when an adverse event is suspected.


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