Hyper-CVAD plus nelarabine in newly diagnosed adult T-cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma

2.1 Patient population

Adult patients with previously untreated or minimally pretreated (failure to one induction course or achieving CR after ≤ 2 cycles) T-ALL/LBL were enrolled (NCT00501826). The study was conducted according to the standards of Good Clinical Practice, per institutional research policies and procedures, and in accordance with the Declaration of Helsinki. Approval was obtained from The University of Texas M.D. Anderson Cancer Center's institutional review board.

Eligible patients had to have an Eastern Cooperative Oncology Group performance status of ≤ 3 and adequate renal and hepatic function [serum creatinine ≤ 2 mg/dL (≤ 2.5 mg/dL acceptable if due to disease), total bilirubin ≤ 2 mg/dL (≤ 5 mg/dL acceptable if due to disease), aspartate aminotransferase and alanine aminotransferase ≤ 4 x upper limit of normal]. All patients provided a written informed consent prior to study enrollment. Patients were diagnosed per the WHO classification criteria and categorized into immunophenotypic subtypes (early, thymic, or mature) as detailed previously.21, 22 Early T-cell precursor (ETP) ALL/LBL was defined by: (1) lack of CD1a and CD8 expression, (2) absent or weak CD5 expression, and (3) expression of at least 1 myeloid (CD11b, CD13, CD33, CD117) or stem cell (CD34, HLA-DR) marker.23 A subset of patients were categorized as non-ETP not otherwise specified (NOS) based on presence of CD5 and CD8 expression, however lack of data on CD1a expression prohibited further subtyping. Complex cytogenetics was defined as ≥3 chromosomal abnormalities in ≥2 metaphases.

2.2 Study design and treatment regimen

This is a single-arm phase 2 study designed to determine the efficacy, measured by CR rate, CR duration (CRD), and OS, and safety of adding nelarabine to hyper-CVAD in newly diagnosed patients with T-ALL/LBL. Therapy consisted of the standard hyper-CVAD regimen as previously described.5 Patients received eight induction-consolidation cycles of hyper-CVAD (cycles 1, 3, 5, 7) alternating with high-dose methotrexate (MTX) and cytarabine (cycles 2, 4, 6, 8) followed by two cycles of nelarabine [650 mg/m² intravenously (IV) daily for 5 days] every 21 to 35 days (Supporting Information Figure S1). After treating 30 patients, the protocol was amended to introduce nelarabine earlier in induction after cycles four and five, in an attempt to prevent early relapses and improve survival (Supporting Information Figure S1).

All patients received CNS prophylaxis consisting of eight intrathecal treatments as previously described.5 Treatment of active CNS leukemia and the indication for therapeutic cranial irradiation have been published.5 Patients with initial bulky mediastinal disease (≥ 7cm) or residual mediastinal disease at the end of the induction/consolidation portion of therapy were considered for local consolidative mediastinal irradiation (XRT; 30–39 Gy over 4 to 5 weeks) after recovery from intensive chemotherapy and prior to the start of maintenance therapy.

Patients received thirty months of 6-mercaptopurine, methotrexate, vincristine, and prednisone (POMP) maintenance chemotherapy as previously detailed.5 Two additional cycles of nelarabine were given instead of cycles 6 and 7 of POMP maintenance as early intensification. MTX (100 mg/m² IV on day 1) plus pegylated-asparaginase (2000 IU/m² IV on day 2; dose reduced to 1000 IU/m² for age >60 years) and hyper-CVAD were given instead of cycles 18 and 19 of POMP maintenance as late intensification (Supporting Information Figure S1). Supportive care measures based on standard institutional practice were provided to all patients.

2.3 Response criteria

For T-ALL, CR was defined as ≤ 5% blasts in the bone marrow (BM) with normalization of peripheral blood counts (ANC ≥ 1 × 10⁹/L and platelet count ≥ 100 × 10⁹/L) and complete resolution of extramedullary disease. Partial response (PR) was defined similarly except for the presence of 6 to 25% BM blasts. For T-LBL and extramedullary disease, CR was defined as complete resolution of all known disease and PR was defined as ≥ 50% reduction in tumor size assessed by computed tomography (CT).

2.4 Disease monitoring and immunophenotyping

For patients with BM involvement, BM evaluation was performed on day 14 of cycle 1 then weekly until remission. Once in CR, BM evaluation was repeated every 4 months. For T-LBL, response was assessed by CT scans after cycle 1 and then repeated every 1 to 2 months until achievement of best response to therapy. Minimal residual disease (MRD) was assessed in remission BM samples using multiparameter flow cytometry with a sensitivity of 0.01%. For MRD analysis, a panel of markers including CD1a, CD2, CD3 (surface and cytoplasmic), CD4, CD5, CD7, CD8, CD10, CD13, CD19, CD33, CD34, CD38, CD45, CD52, CD117, HLA-antigen D related (HLA-DR), myeloperoxidase, and terminal deoxynucleotidyl transferase were assessed on at least 200,000 aspirated nucleated BM cells.

2.5 Safety assessment

Adverse effects were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Guidelines for dose modifications were previously detailed.5 Nelarabine was dose reduced to 650 mg/m² IV on alternate days (1, 3, 5) for patients who develop grade 2 therapy-related neurotoxicity or have grade 1 or 2 neurotoxicity prior to nelarabine courses. Nelarabine was discontinued for grade ≥ 3 neurotoxicity except for somnolence, malaise, fatigue, or lethargy that resolve within 24 hours

2.6 Statistical analysis

Differences in the distribution of variables among subgroups were analyzed using x-squared and Mann-Whitney U tests (or Fisher exact tests). OS was calculated from start of therapy until date of death or last follow-up. CRD was measured from date of CR until relapse, death, or last follow-up; death in CR was a censored event. OS and CRD curves were plotted using Kaplan-Meier method and compared using the log-rank test.

3.1 Patient characteristics

From August 2007 to May 2016, 67 patients with T-ALL/LBL were enrolled; 40 patients (60%) had T-ALL, 26 (39%) had T-LBL, and 1 (1%) had biphenotypic disease. Patient characteristics are summarized in Table 1. Median age was 37 years (range, 18–78) with male predominance. At diagnosis, four patients (6%) had CNS involvement and 34 (51%) had mediastinal disease. Median white blood cell (WBC) count at presentation was 7.8 × 10⁹/L (range, 0.8–309.2) and 11 patients (16%) had a WBC count >100 × 10⁹/L. Of 65 patients with sufficient immunophenotyping data, 25 (37%) were categorized as thymic, 15 (22%) as ETP, 12 (18%) as early non-ETP, 9 (13%) as mature, and 4 (6%) as NOS. Forty-one patients (61%) had diploid and 12 (18%) had complex karyotype by conventional cytogenetics. Mutational analysis demonstrated wild-type TP53 in all 17 (25%) tested patients.

3.2 Efficacy and response rates

Twelve patients (18%; T-ALL, N = 10; T-LBL, N = 2) received prior hyper-CVAD therapy and were in CR at the time of enrollment. Among the remaining 55 patients, the overall response rate was 96% of which 51 patients (93%) achieved CR and 2 (4%) achieved PR. There was no difference in the CR rate in ETP versus non-ETP subtypes (93% and 94%, respectively; P = .93), with a median time to CR of 1.2 months (range, 0.4–8.4). Among the T-ALL patients who achieved CR (N = 36), 83% became MRD negative, of which 47% achieved MRD negativity at the time of CR.

After a median follow-up of 42.5 months (range, 4–110), 42 patients (63%) remain alive of which 37 (55%) are still in CR; including two patients taken off study due to MRD relapse and chronic pleural effusion precluding MTX administration (Supporting Information Figure S2). Eleven patients (7 ETP, 3 early non-ETP, 1 thymic with complex karyotype) received allogeneic stem cell transplantation (SCT) after achieving first CR (CR1) and remain alive post SCT. Of these patients, 9 remain in CR and 2 relapsed post SCT.

Twenty-one patients (31%) relapsed (T-ALL, N = 13; T-LBL, N = 8) with a median time to relapse of 7.3 months (range, 1.4–62). All patients achieved CR prior to relapse including 10 T-ALL (77%) patients achieving MRD negativity. Sites of relapse included 12 hematologic (peripheral blood and BM), 5 extramedullary (EM; 4 mediastinal and 1 rib), 3 BM plus EM (2 adenopathy and 1 mediastinal), and 1 BM plus CNS in distribution.

Of the 34 patients with mediastinal disease at presentation, 20 (59%) received XRT following induction/consolidation. The remaining 14 patients (41%) did not receive XRT due to relapse (N = 4), noncompliance/refusal (N = 3), withdrawal of consent (N = 2), SCT (N = 2), physician choice (N = 1), congestive heart failure (N = 1), and failure to meet XRT criteria (N = 1). Two relapses, including 1 mediastinal relapse, occurred among those who received XRT compared to 5 relapses, 3 mediastinal in distribution, in patients who did not receive XRT.

Twenty-five patients died (37%), including 1 partial responder and 1 nonresponder dying after third salvage therapy off study. The remaining deaths occurred in the CR group; causes of death were relapse (N = 18), secondary acute myeloid leukemia (AML; N = 3), intracranial hemorrhage (N = 1), and unknown etiology (N = 1), the latter two patients died in CR. Early deaths (within the first month) did not occur. Among the 3 secondary AML patients, 2 had AML and 1 patient had mixed phenotype acute leukemia (myeloid/B-cell lineage) with no evidence of T-cell disease.

3.3 Survival

The 3-year probability of CRD and OS for the whole cohort was 66% (95% CI: 52–77) and 65% (95% CI: 51–76), respectively, with a median OS of 82 months (Figure 1A,C). There was a nonsignificant statistical improvement in the CRD (69% vs 63%, P = .54) and OS (71% vs 62%, P = .41) for patients with T-LBL when compared to T-ALL (Figure 1A,C). When analyzed by immunophenotype, no significant differences in CRD or OS were observed among the various subsets (Figure 1B,D). Unlike previous reports, presenting WBC count had no impact on OS (Figure 2A).24 Similarly, there was no difference in OS between the two different nelarabine regimens (Figure 2D). Patients with complex cytogenetics (≥ 3 chromosomal abnormalities) had significantly inferior CRD and OS when compared to patients with noncomplex karyotype (Figure 2B,C).

3.4 Safety and toxicity

Grade ≥ 3 nonhematological treatment emergent adverse events were reported in 91% of patients with the most common toxicities including infections (84%), hypokalemia (46%), and hypophosphatemia (40%) (Supporting Information Table S1). Fifty-five patients (82%) received nelarabine (1 cycle, N = 7; 2 cycles, N = 19; 3 cycles, N = 8; 4 cycles, N = 21). The remaining 12 patients did not receive nelarabine due to: early relapse (N = 4), withdrawal of consent (N = 3), no response (N = 2), SCT (N = 1), patient's choice (N = 1), and death (N = 1). Seventy-two percent of patients experienced at least one form of neurotoxicity. The most common neurotoxicities were peripheral neuropathy (69%), headache (6%), and altered mental status (AMS; 4%). The majority of the neurotoxicities were grade 1 and 2 in severity. Five patients (7%) experienced grade ≥ 3 neurotoxicity including AMS (N = 2), headache (N = 1), peripheral neuropathy (N = 1), and nelarabine-related pain (N = 1). The incidence of neurotoxicity was similar for both nelarabine regimens [regimen 1, N = 24 (80%); regimen 2, N = 24 (65%)].

3.5 Comparison with historical hyper-CVAD data

To help us determine the role of nelarabine in the frontline setting, we compared these results to our historical hyper-CVAD data. Newly diagnosed T-ALL/LBL patients treated at our institution on four prospective clinical trials from 1992 to 2007 with hyper-CVAD alone (ID02–230, CPPDM92-048, DM93-077, and DM99–414) were reviewed. This group included patients treated with the standard and modified hyper-CVAD regimens. Details regarding these regimens were previously described.5 We compared both cohorts with regards to baseline characteristics, CRD, and OS (Table 1). Subset analysis comparing both regimens by diagnosis (T-ALL vs T-LBL) and by immunophenotype (ETP vs Non-ETP) was performed.

We found no difference in CRD and OS for the whole cohort with the addition of nelarabine (Figure 3A,B). In patients with T-LBL there was a trend toward superior CRD with the use of hyper-CVAD alone which did not translate into an improvement in OS (Figure 3C,D). However in T-ALL patients, there was a nonsignificant improvement in the CRD with the combination regimen without an improvement in OS (Figure 3E,F). In ETP-ALL/LBL patients, the 3-year OS and CRD was higher using the combination regimen, although these were not statistically significant (P-values, .28 and .67, respectively) (Figure 3G,H).

CONCEPTION AND DESIGN

Farhad Ravandi, Stefan Faderl, Hagop M. Kantarjian

PROVISION OF STUDY MATERIALS OR PATIENTS

Farhad Ravandi, Hagop M. Kantarjian, Stefan Faderl, Elias Jabbour, Nitin Jain, Deborah Thomas, Tapan Kadia, Gautam Borthakur, Joseph D. Khoury, Jan Burger, William Wierda, Susan O'Brien, Marina Konopleva, Alessandra Ferrajoli, Partow Kebriaei, Bouthaina Dabaja, Steven Kornblau, Yesid Alvarado, Naval Daver, Naveen Pemmaraju, Prithviraj Bose, Philip Thompson, Hind Al Azzawi, Mary Kelly, Preteesh Jain, Guillermo Garcia-Manero, Jorge Cortes

COLLECTION AND ASSEMBLY OF DATA

Rebecca Garris, Mary Kelly, Yasmin Abaza, Joseph D. Khoury, Hind Al-Azzawi.

DATA ANALYSIS AND INTERPRETATION

Yasmin Abaza, Rebecca Garris, Farhad Ravandi, Hagop M. Kantarjian

MANUSCRIPT WRITING

Yasmin Abaza, Farhad Ravandi

FINAL APPROVAL OF MANUSCRIPT

Farhad Ravandi, Yasmin Abaza, Hagop M. Kantarjian and all authors