Crizotinib in Combination With Chemotherapy for Pediatric Patients With ALK+ Anaplastic Large-Cell Lymphoma: The Results of Children's Oncology Group Trial ANHL12P1

PURPOSE

Arm crizotinib (CZ) of the Children's Oncology Group trial ANHL12P1 (ClinicalTrials.gov identifier: NCT01979536) examined the efficacy and toxicity of adding CZ to standard chemotherapy for children with newly diagnosed, nonlocalized ALK+ CD30+ anaplastic large-cell lymphoma (ALCL).

PATIENTS AND METHODS

Between 2013 and 2019, 66 enrolled children received CZ with chemotherapy. Patients received a 5-day prophase followed by six chemotherapy cycles at 21-day intervals with CZ administered twice daily during each 21-day cycle. The study was temporarily closed for two periods (total 12 months) to evaluate toxicity, during which CZ was discontinued. Measurements of NPM-ALK fusion transcripts in peripheral blood were performed at diagnosis for minimal disseminated disease (MDD).

RESULTS

The 2-year event-free survival (EFS) is 76.8% (95% CI, 68.5 to 88.1) and the 2-year overall survival is 95.2% (95% CI, 85.7 to 98.4). Fifteen patients relapsed and one patient died; median time to relapse was 7.4 months from diagnosis, with relapses occurring after chemotherapy was complete. The 66 patients completed 384 cycles of chemotherapy. Thirteen of the 66 patients experienced a grade 2+ thromboembolic adverse event (19.7%; 95% CI, 11.1 to 31.3). In the 25 patients who received mandated prophylactic anticoagulation, there were two thromboembolic events (8.0%; 95% CI, 0.01 to 26). Patients with negative MDD had a superior outcome, with an EFS of 85.6% (95% CI, 68.6 to 93.8); positive MDD was associated with a lower EFS of 58.1% (95% CI, 33.4 to 76.4).

CONCLUSION

Arm CZ of ANHL12P1 demonstrated that the addition of CZ to standard treatment prevented relapses during therapy for children with ALCL, MDD predicted EFS, and the addition of CZ resulted in unexpected thromboembolic events. Overall survival and EFS rates are consistent with the highest reported outcomes for children with ALCL.

INTRODUCTION

Anaplastic large-cell lymphoma (ALCL) is a rare form of mature T-cell non-Hodgkin lymphoma characterized by uniform overexpression of CD30 that accounts for 15% of all childhood lymphomas.^1,2 Previous clinical trials have explored different treatment protocols for ALCL (Data Supplement, online only). A 30% failure rate for initial therapy has persisted despite variations in medications, intensity, and length of treatment.^3-11 Disease recurrence during initial therapy is difficult to treat even with an allogeneic stem-cell transplant.^12,13 Interventions that prevent relapse or disease progression could therefore improve survival.

CONTEXT

• Key Objective

• Anaplastic large-cell lymphoma is characterized by a translocation involving the anaplastic large-cell lymphoma kinase (ALK) gene in almost all pediatric cases. Crizotinib (CZ) inhibits ALK, offering hope to improve the 30% failure rate that has existed for the past 30 years. The objective of the study was to determine if CZ could be safely added to chemotherapy and improve outcome.

• Knowledge Generated

• The event-free survival for patients who received CZ with chemotherapy was higher than that reported in most previous studies and similar to that reported in a previous report using brentuximab vedotin with chemotherapy. Unfortunately, 20% of patients on the CZ arm experienced a thromboembolic event if they were not receiving anticoagulation.

• Relevance (S. Bhatia)

• Given the risk of CZ-associated thromboembolic events, brentuximab may continue to be the preferred agent. Further research needs to examine the use of CZ with other agents in frontline settings, particularly if thromboprophylaxis can mitigate the thromboembolism risk.*

  *Relevance section written by JCO Associate Editor Smita Bhatia, MD, MPH.

The WHO classifies ALCL into two distinct subgroups on the basis of the chromosomal translocation involving the anaplastic large-cell lymphoma kinase (ALK) gene: ALK-positive (ALK+) ALCL and ALK-negative (ALK–) ALCL.³ The oncogenic tyrosine kinase encoded by the ALK fusion protein is critical for the pathogenesis of pediatric ALCL. The majority of pediatric cases, > 95%, express ALK.⁴

Crizotinib (CZ) is a small molecule inhibitor of several receptor tyrosine kinases including ALK and potently inhibits cell proliferation in ALK-positive ALCL cells.^5-7 In children with relapsed or refractory ALCL, the use of CZ resulted in a 90% overall response rate after two cycles.⁸ Common adverse reactions to CZ include vision disorder, nausea/vomiting, diarrhea, edema, and constipation. Combining CZ with chemotherapy in children resulted in neutropenia, nausea, and dehydration but no other significant toxicities.⁹

The primary aim of arm CZ of ANHL12P1 was to determine the tolerability of CZ administered in combination with standard chemotherapy (ALCL99) and to estimate the event-free survival (EFS) and overall survival (OS) with this therapy.

PATIENTS AND METHODS

Study Design

ANHL12P1 was a randomized phase II study with the primary aim to determine the toxicity and efficacy of the addition of brentuximab vedotin (BV; arm BV)¹⁰ or CZ (arm CZ) to standard chemotherapy in children with newly diagnosed, nonlocalized, ALK+/CD30+ ALCL. Patients with a body surface area < 0.9 m² were not eligible to be randomly assigned to arm CZ because of difficulties in dosing CZ in smaller patients. Assignment to arm CZ was by randomized assignment for patients with a body surface area ≥ 0.9 m². ANHL12P1 was approved by the National Cancer Institute (NCI) Central Institutional Review Board and the institutional review boards of the participating institutions. Informed written consent for study participants was obtained from the participant or parent or guardian before starting protocol therapy in accordance with the US Department of Health and Human Services guidelines.

Patients

Eligible patients had histologically proven ALK+ ALCL and were age < 22 years at diagnosis. Eligible patients had stage II, III, or IV disease according to the St Jude staging system. Patients with disease isolated to the skin, stage I disease, or central nervous system involvement were not eligible. Additional exclusion criteria included previous cytotoxic chemotherapy, known immunodeficiency, organ transplant recipient, pregnant female, known HIV-positive status, and weight < 10 kg. Previous steroid treatment and/or radiation treatment was allowed only for emergent management of a mediastinal mass. Patients receiving medications known to be metabolized by CYP3A4 with narrow therapeutic indices were not eligible because of drug interactions. All patients underwent physical examination, computed tomography scans, bone marrow examination, and cerebrospinal fluid examination to determine the extent of disease. ¹⁸F-labeled fluorodeoxyglucose positron emission tomography could be used for disease evaluation but was not mandated by the study.

Treatment Protocol

Eligible patients received chemotherapy on the basis of the ALCL99 Protocol (online only) (Table 1). Treatment duration was 5 months. No patient received radiation. Growth factors could be used at the treating physician's discretion.

TABLE 1.

Chemotherapy Schedule

CZ was administered daily, orally on days 1-21 of each of the six 21-day cycles and stopped for delays in starting subsequent cycles. The starting dose was 165 mg/m²/dose. The CZ formulation used was formulated capsules of 200 and 250 mg administered at dose levels of 250 mg once daily, 200 mg twice a day, 250 mg once each morning and 200 mg once each evening, and 250 mg twice a day. Dose reductions by one level were mandated for certain toxicities (Data Supplement).

Patients were evaluated for response after cycles 2 and 6. Complete response (CR) was defined as the disappearance of all evidence of disease. CR (unconfirmed) was defined as a residual lymph node mass > 1.5 cm that regressed by > 75% in the sum of the products of the greatest perpendicular diameters or returned to normal size or any residual lesion in organs that decreased by > 75% with a negative positron emission tomography scan. Partial response was defined as a > 50% decrease in the sum of the products of the greatest perpendicular diameters of the lesions with no new lesions. Patients were declared off protocol therapy if they developed progressive disease at any time. After completion of therapy, follow-up was performed every 3 months for the first year, then every 6 months during years 2 and 3, and then yearly. All relapses were to be confirmed by biopsy.

Toxicity Assessment

Adverse events and clinically significant laboratory findings were collected using NCI Common Terminology Criteria for Adverse Events (version 4.0). Reporting was done through the NCI Adverse Event Expedited Reporting System. Required reporting included all nonhematologic, nontargeted toxicities ≥ grade 3, all grade 2 or higher thromboembolic events, and all hematologic and nonhematologic toxicities that resulted in hospitalization or delay in therapy. Patients were monitored weekly during therapy. Serum chemistries including aspartate aminotransferase, alanine aminotransferase, and bilirubin were obtained weekly during cycles 1 and 2, and then at the start of each cycle. An echocardiogram and an electrocardiogram were obtained before each dose of doxorubicin.

Pathology

Institutional phenotyping (by flow cytometry or immunohistochemical staining) was required to confirm the diagnosis. All cases were required to be positive for CD30 and ALK. ALK positivity was determined at the institutional level, with either immunohistochemical staining or fluorescence in situ hybridization acceptable.

Correlative Biology Studies

Serial assessments of the t(2;5) (p23;q35) NPM-ALK fusion transcript were evaluated in the research reference laboratory using quantitative reverse transcriptase polymerase chain reaction. Although the specific cellular localization of ALK was not assessed, on the basis of the frequency of NPM-ALK rearrangements, which represent approximately 85%-90% of ALK+ ALCLs in the pediatric population,¹¹ the assessment was focused on NPM-ALK fusion transcripts for the analysis of minimal disseminated disease (MDD). Peripheral blood samples were obtained at baseline, on day 1 of cycle 1, and on day 1 of cycle 2. Peripheral blood was shipped overnight within 24 hours of collection to the research reference laboratory for analysis. Quantitative reverse transcriptase polymerase chain reaction was performed by extracting total RNA from peripheral blood specimens. The normalized copy numbers were expressed as copy numbers of NPM-ALK per 10⁴ copies of ABL as previously published.¹⁴ MDD was defined as > 10 normalized copy number at baseline.

Statistical Analysis

The primary study end points were the occurrence of grade 3+ nonhematologic adverse events and EFS. All patients assigned to arm CZ who received protocol therapy contributed to the primary EFS analysis. EFS was defined as the time from study entry until disease progression, relapse, or death. EFS was compared with a historical control cure model with cure rate of 70% and exponential failures with exponent 1.5. A sample size of 64 eligible patients would provide the study 90% power to detect a hazard ratio of 0.5 (cure rate improved to 84%) using the log-rank test at a one-sided significance level of 0.10. Only patients who received at least one dose of CZ contributed to the toxicity analysis. A 5% rate of grade 4+ liver toxicity was considered acceptable with a true rate of 15% unacceptable. All P values were two-sided unless otherwise specified (Data Supplement).

RESULTS

Patient Characteristics

ANHL12P1 enrolled 69 patients on arm CZ between December 6, 2013, and January 18, 2019. On July 13, 2016, arm CZ was temporarily closed because of toxicity and was reopened on October 31, 2016, with amendment 5, which updated the risks of the study to include thromboembolic events. Arm CZ was temporarily closed to accrual from April 4, 2017, until January 22, 2018, when it reopened with amendment 6, which required prophylactic anticoagulation because of thromboembolic events. On February 8, 2019, the stopping rule for thromboembolic events was met and the study was closed to accrual. Patients who were receiving therapy at the time of the closures (April 4, 2017, and February 8, 2019) remained on study but were required to stop taking CZ. The 69 patients were enrolled at 51 separate Children's Oncology Group (COG) sites. Data as of March 31, 2021, are included in this report. One patient assigned to arm CZ did not receive any treatment and withdrew consent for further data submissions. Sixty-eight remaining patients were included in the analysis. Two patients did not receive any CZ and were withdrawn during prophase (one at the treating physician's discretion and one for refusal by patient/parent/guardian), leaving 66 eligible patients for toxicity evaluation (Fig 1). Baseline characteristics are listed in Table 2.

FIG 1.

Flow diagram. BSA, body surface area; BV, brentuximab vedotin; CZ, crizotinib; EFS, event-free survival.

TABLE 2.

Clinical Characteristics of 68 Children With Anaplastic Large-Cell Lymphoma

Treatment and Toxicity

Overall, 66 patients on arm CZ received at least one dose of CZ with 384 cycles of chemotherapy completed. Growth factor was given in 203 of 384 (52.9%) cycles. Sixty-two patients completed all six cycles, and four patients came off protocol therapy early. One patient discontinued protocol therapy during cycle 1 because the physician determined that it was in the patient's best interest (patient was unable to swallow pills); one patient withdrew consent after cycle 3; one patient was removed from treatment during cycle 3; and one patient ended treatment after cycle 5 because the physician determined that it was in the patient's best interest. No patient gave the reason “Adverse events requiring removal from protocol therapy” for coming off protocol therapy.

The median interval between each cycle was 22 days with an interval > 28 days (ie, delayed more than 1 week) in only 14 of 384 (3.6%) cycles. There were 125 of 384 cycles (32.5%) among 45 of 66 patients where < 90% of CZ was administered. Of those 125 cycles, 47 (37.6%) were due to the mandated cessation of CZ when the protocol was placed on clinical hold or met the stopping rule for further accrual.

Toxicity is summarized in Table 3. Grade 4 liver toxicity occurred in two patients (3%), which was considered acceptable. Nonhematologic grade 3 or 4 toxicities that occurred in more than 5% of patients or cycles included febrile neutropenia, oral mucositis, hypokalemia, ALT elevation, hypophosphatemia, infection, and thromboembolic events. There were no toxic deaths, no cases of visual disturbances, and no cases of liver failure. Interim analyses concluding liver toxicity was acceptable took place at 29.7% (19 patients), 48.4% (31 patients), and 89.1% (57 patients) of the expected information (Data Supplement).

TABLE 3.

Grade 3 and 4 Toxicities Experienced on Arm Crizotinib of ANHL12P1

Thirteen of the 66 patients who received CZ experienced a grade 2+ thromboembolic adverse event during treatment (19.7%; 95% CI, 11.1 to 31.3), as summarized in Table 4. There were 41 patients who received at least one cycle of CZ before the required prophylactic anticoagulation was introduced in amendment 6. Eleven of the 41 patients (26.8%; 95% CI, 14.2 to 42.9) experienced grade 2+ thromboembolic adverse events. Two patients of the 25 patients enrolled after amendment 6 experienced grade 2+ thromboembolic adverse events (8.0%; 95% CI, 0.01 to 26.0). Four unique patients experienced a grade 2+ adverse event of a pulmonary embolism (6.1%; 95% CI, 1.7 to 14.8). All four patients were enrolled before amendment 6.

TABLE 4.

Thromboembolic Toxicities Experienced on Arm Crizotinib of ANHL12P1

Outcome

Sixteen patients experienced events: 15 patients with disease relapses and 1 death. Fifty-two patients did not experience an event and were censored on the last date of contact. The death occurred in a patient who came off therapy after prophase and did not receive any CZ. Twelve of the 15 relapses (80.0%) occurred within 12 months of initial diagnosis. Only one patient of 68 (1.5%) relapsed before off-therapy evaluation. This relapse occurred 4.2 months from diagnosis during the sixth cycle of chemotherapy. Relapses were confirmed by biopsy in all 15 cases. Median time from diagnosis to relapse was 7.4 months (range, 4.2-28.9 months). There were no relapses involving the CNS.

The CR rate (CR and CR unconfirmed) for patients who underwent evaluation was 91.7% after cycle 2 (55 of 60 patients) and 98.3% after cycle 6 (59 of 60 patients).

The 2-year EFS estimate was 76.8% (95% CI, 68.5 to 88.1), P = .14 compared with the historical EFS of 70%. The 2-year OS was 95.2% (95% CI, 85.7 to 98.4; Fig 2). The median follow-up for patients alive at last contact was 3.4 years.

FIG 2.

(A) EFS (2-year EFS 76.8%; 95% CI, 68.5 to 88.1) and (B) OS (2-year OS 95.2%; 95% CI, 85.7 to 98.4) for newly diagnosed patients with ALK+ anaplastic large-cell lymphoma treated with CZ and chemotherapy. CZ, crizotinib; EFS, event-free survival; OS, overall survival.

Prognostic Factors

Prognostic factors of EFS were evaluated for the entire cohort of patients in univariate analysis. No clinical factors were associated with EFS: age (P = .807), sex (P = .512), ethnicity (P = .276), stage (P = .344), bone involvement (P = .346), bone marrow involvement (P = .575), lung involvement (P = .21), skin involvement (P = .991), soft tissue involvement (P = .846), and spleen involvement (P = .791).

Twenty-eight patients received < 80% of the total combined CZ dose for all six cycles. Using time-dependent covariates,¹⁵ there was no statistical difference (P = .65) in the 2-year EFS between the group of patients who received ≥ 80% of total CZ (eight relapses; EFS, 81.4% [95% CI, 64.9 to 90.7%]) and those who received < 80% of total CZ (seven relapses; EFS, 71.7% [95% CI: 49.3 to 85.6]). Using a cutoff of 90% of total CZ dose was also not statistically significant (P = .38).

Of the 68 patients, 57 had available baseline MDD data and were included in the analyses. The missing 11 samples represent those in which there was inadequate RNA quality or quantity (4) for NPM-ALK quantification (7). The 57 patients with MDD were not statistically different in age, sex, race, and baseline disease characteristics from the 11 patients without MDD data (Data Supplement). MDD measured in peripheral blood was highly predictive of EFS (P = .0058). The 2-year EFS estimate was 85.6% (95% CI, 68.6 to 93.8) for MDD-negative (n = 37) patients and 58.1% (95% CI, 33.4 to 76.4) for MDD-positive (n = 20) patients (Fig 3).

FIG 3.

(A) EFS and (B) OS of newly diagnosed patients with ALK+ anaplastic large-cell lymphoma treated with crizotinib and chemotherapy according to baseline MDD (n = 57; MDD-negative = 37; MDD-positive = 20). EFS, event-free survival; OS, overall survival.

DISCUSSION

Over several decades, multiple treatment strategies for ALCL in children have resulted in similar outcomes. Variations in chemotherapeutic agents or treatment intensity have not resulted in improvements in EFS.^16-18 More recently, agents that target the oncogenic driver of ALK+ ALCL, such as CZ, have shown remarkable benefit prolonging survival for patients with relapsed disease.^5-8,19

Our report describes the trial results of adding CZ to standard ALCL chemotherapy. The results were favorable, with a 2-year EFS estimate of 76.8% and a 2-year OS of 95.2% (Fig 2). Similar to previous trials, most relapses occurred soon after the end of planned chemotherapy; average time from the start of chemotherapy to relapse was 7.4 months, compared with 6.5 months in the vinblastine-free arm of ALCL99.¹⁷ In our study, no patient progressed or recurred while receiving therapy. In previous trials, those patients who relapse or progress during treatment experience the poorest outcomes. The prevention of relapse during treatment may indicate the effectiveness of CZ to prevent on-therapy relapse. This effect was similar to observations on the BV arm of this trial.¹²

Assessment of the t(2;5) (p23;q35) NPM-ALK fusion transcript in peripheral blood samples were evaluated for MDD. Patients who were MDD-positive at the start of treatment had a significantly lower 2-year EFS of 58% (Fig 3). This finding confirms the results of previous studies^20-22 suggesting that patients with less favorable disease can be distinguished during initial therapy, providing an opportunity to offer these patients new frontline treatments in an effort to improve outcomes.

Addition of CZ to standard chemotherapy resulted in one unexpected toxicity: 20% of patients who received CZ experienced a thromboembolic event during treatment (Table 4). Four of these patients had a pulmonary embolism. After prophylactic anticoagulation was required for all patients, two of the next 25 (8%) had thromboembolic events with no further pulmonary emboli. CZ has been previously associated with thrombosis at low levels when used as a single agent, or in combination with other agents. Initial trials of CZ as a single agent in pediatrics described 5% or less of patients experiencing thrombotic complications^9,23 and use in adults with non–small-cell lung cancer is associated with a 3% incidence of pulmonary embolus. The ALCL99 regimen has not been associated with a high incidence of thrombosis or thromboembolism,²⁴ suggesting that this effect may be attributed to the addition of CZ. The unexpectedly high incidence of thrombosis observed in this trial may have been exacerbated by the presence of central venous catheters in all patients; however, patients on the BV arm of this study also had central venous catheters and received the same chemotherapy backbone without a similar increase in thrombosis.¹⁰ The only notable difference in patients between arm CZ and arm BV was slightly older median age in arm CZ (14 v 12 years), a difference unlikely to explain the difference in thromboembolic events. In addition, we were unable to identify any additional risk factor in the patients who had a thrombotic event. The elevated incidence of thrombosis was mitigated by prospective anticoagulation therapy. Future regimens combining CZ with multiagent chemotherapy should consider an anticoagulation prophylactic regimen.

One study limitation was the lack of central review of pathologic specimens and subtype classification for most patients on the trial. The effect of CZ on outcome of individual subtypes could therefore not be assessed.

Brentuximab-based chemotherapy is a new standard of care in adults with ALCL on the basis of the ECHELON-2 trial, which showed a significant increase in progression-free survival for patients treated with brentuximab, cyclophosphamide, doxorubicin, and prednisone, compared with those treated with cyclophosphamide, doxorubicin, vincristine, and prednisone. Brentuximab also improved EFS in children with ALCL. Although both arms of ANHL12P1 had excellent EFS, the trial was not designed to directly compare arm CZ with arm BV. Given the increased rate of thromboembolic events associated with CZ, it is unlikely to be preferred over brentuximab given on the chemotherapy backbone used in this trial. CZ's activity in ALCL does warrant consideration for use in frontline ALCL potentially in combination with brentuximab alone, rather than as part of a multiagent chemotherapy regimen.

In summary, arm CZ of ANHL12P1 reports that the addition of CZ to a standard chemotherapy backbone for ALCL in children prevented on-therapy disease relapse and provided EFS and OS rates at least as good as previous chemotherapy regimens. An unexpected increase in the number of thromboembolic events was observed. Detection of MDD at the start of treatment has significant predictive value and should be incorporated into initial staging of disease and selection of treatment. Our study enrolled 69 patients from 51 different COG sites across the country, showing that a clinical trial to test new agents is possible in a rare disease. Continued collaboration to develop new treatment approaches for childhood ALCL will be critical in providing next-generation strategies using CZ and other targeted agents.

DATA SHARING STATEMENT

The Children's Oncology Group Data Sharing policy describes the release and use of COG individual subject data for use in research projects in accordance with National Clinical Trials Network (NCTN) Program and NCI Community Oncology Research Program (NCORP) Guidelines. Only data expressly released from the oversight of the relevant COG Data and Safety Monitoring Committee (DSMC) are available to be shared. Data sharing will ordinarily be considered only after the primary study manuscript is accepted for publication. For phase III studies, individual-level deidentified data sets that would be sufficient to reproduce results provided in a publication containing the primary study analysis can be requested from the NCTN/NCORP Data Archive at https://nctn-data-archive.nci.nih.gov/. Data are available to researchers who wish to analyze the data in secondary studies to enhance the public health benefit of the original work and agree to the terms and conditions of use. For non–phase III studies, data are available following the primary publication. An individual-level deidentified data set containing the variables analyzed in the primary results paper can be expected to be available upon request. Requests for access to COG protocol research data should be sent to: datarequest@childrensoncologygroup.org. Data are available to researchers whose proposed analysis is found by COG to be feasible and of scientific merit and who agree to the terms and conditions of use. For all requests, no other study documents, including the protocol, will be made available and no end date exists for requests. In addition to above, release of data collected in a clinical trial conducted under a binding collaborative agreement between COG or the NCI Cancer Therapy Evaluation Program (CTEP) and a pharmaceutical/biotechnology company must comply with the data sharing terms of the binding collaborative/contractual agreement and must receive proper approvals.

AUTHOR CONTRIBUTIONS

Conception and design: Eric J. Lowe, Anne F. Reilly, Megan S. Lim, Thomas G. Gross, Sarah Alexander, Catherine M. Bollard

Provision of study materials or patients: Catherine M. Bollard

Collection and assembly of data: Eric J. Lowe, Anne F. Reilly, Megan S. Lim, Lauren Saguilig, Donald A. Barkauskas, Rui Wu

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Crizotinib in Combination With Chemotherapy for Pediatric Patients With ALK+ Anaplastic Large-Cell Lymphoma: The Results of Children's Oncology Group Trial ANHL12P1

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