Outcome of adults with relapsed/refractory T‐cell acute lymphoblastic leukemia or lymphoblastic lymphoma

To the Editor: T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are two different manifestations of the same neoplasm derived from immature lymphoid cells of T-cell lineage, and classified according to extent of bone marrow involvement.1 Despite a high complete remission (CR) rate obtained with frontline therapy, most patients eventually relapse. Historically, the prognosis of patients with relapsed/refractory (R/R) ALL has been dismal with long term survival rate of <10%.2 Unlike the recent therapeutic progress in R/R B-ALL, salvage options for T-ALL are limited. Little is known about outcome of patients with R/R T-ALL treated with contemporary salvage regimens. Herein, we report the outcome of adults with R/R T-ALL treated at our institution over the past decade. The goal of this analysis is to identify factors predictive for long-term survival and to establish the benchmark for expected outcomes in this setting. We reviewed clinical characteristics and treatment outcomes of 82 patients with R/R T-ALL who received salvage therapy at the University of Texas MD Anderson Cancer Center between July 2009 and December 2019. All patients provided informed consent for treatment according to institutional guidelines and the Declaration of Helsinki. This retrospective study was approved by the Institutional Review Board. In order to avoid double counting patients who received more than one salvage throughout their course of therapy, and to better illustrate outcome of salvage therapy while minimizing group heterogeneity, patients were classified according their disease status at the time of first therapy received at our institution for relapsed/refractory disease. Early T-cell precursor (ETP) was defined as CD1a(-), CD8(-), CD5 < 75% expression, with positivity for one or more stem cell or myeloid antigens. Response assessment was according to standard criteria for ALL. Measurable residual disease (MRD) was assessed at the time of complete response by multiparameter flow cytometry with a sensitivity of 0.01%. Baseline characteristics at the time of presentation for salvage therapy are summarized in Supplementary Table 1. The median age was 37 years (range 14-77 years). Patients had received a median of two prior therapies (range, 1-9): 32 patients (39%) were in first salvage (S1), 22 (27%) were in second salvage (S2), and 28 (34%) were in third salvage or beyond (S3+). Sixty-seven patients (82%) had T-ALL and the rest had T-LBL. ETP subtype was present in 35% of cases. Twelve patients (16%) had complex cytogenetics (≥5 chromosomal abnormalities). Salvage therapies are detailed in Supplementary Table 2. Fifty-eight patients (59%) received standard of care regimens, including nelarabine-based therapy in 21 patients (26%), pediatric-inspired asparaginase-based therapy in 11 patients (13%), and clofarabine-based therapy in 9 patients (11%). Thirty-four patients (41%) received investigational-based therapies, mainly venetoclax-containing regimens (18 patients [22%]). Overall, the composite CR/CR with incomplete hematologic recovery (CRi) rate to salvage therapy was 46%. Higher response rates were observed in S1 than in later lines of salvage (63% in S1, 27% in S2 and 43% in S3+, P = .034). Among the 12 patients treated in fourth salvage or beyond, none responded. The MRD negativity rate among responders was 51% (18/35 tested patients). The median duration of response was 4 months (95% confidence interval [CI], 1-78 months). Among the 18 patients who received venetoclax plus chemotherapy combination, the CR/CRi and MRD negativity rates were 72% and 58% (7 out 12 tested patients), respectively. Overall, 16 patients (20%) received subsequent consolidative HSCT, within a median time from remission to HSCT of 3.3 months (range, 1.3-6.5 months) [Supplementary Figure 1]. With a median follow-up of 37 months (range, 1-79 months), the median overall survival (OS) for the entire cohort was 8 months (95% CI, 5-10 months), and the 2-year OS rate was 23% [Figure 1A]. Survival was similar in patients treated in S1 or S2 whereas patients in S3+ had worse outcome (2-year OS rates 29%, 29%, and 11%, in S1, S2, and S3+, respectively, P = .159) [Figure 1B]. Fourteen patients (17%) were alive in CR/CRi at their last follow-up. Among the 27 patients who underwent subsequent HSCT, 18 (67%) had an OS rate >1 year; 11 (41%) were alive in remission at their last follow-up, at a median of 33 months from transplant date (range, 4-86 months). Among patients who did not undergo subsequent HSCT, 7 patients (13%) had an OS rate >1 year, and 3 patients (5%) were alive in remission at last follow-up, at a median of 2 months from the time of achieving remission (range, 1-4 months). As expected, response to salvage therapy was associated with better survival (2-year OS rate of 37% in responders vs. 10% in non-responders, P < 0.001) [Figure 1C ]. A 3-month landmark analysis showed a significant survival benefit of consolidative HSCT among patients who achieved CR with salvage therapy (2-year OS rates of 56% vs. 24%, P = .002). [Figure 1D]. In order to determine prognostic factors for survival, we performed univariate and multivariate analyses using the following baseline characteristics: age, disease type (T-ALL vs. T-LBL), imunophenotypic subtype (ETP vs. non-ETP), presence of complex cytogenetics, presence of CNS disease at salvage, duration of first CR < or ≥ 6 months, and line of salvage (S1/S2 vs. S3+). [Supplementary Table 3]. The only predictor for better survival was earlier salvage therapy (S1/S2 vs. S3+: hazard ratio 0.57, 95% CI 0.33-0.99, P = .049). The current study shows poor outcome of adults with R/R T-ALL or LBL with CR/CRi rate to contemporary salvage therapy of 46%, and a median survival of 8 months. Unlike the frontline setting where disease biology (eg, immunophenotype or cytogenetic abnormalities) strongly impacts survival, our analysis did not identify any baseline characteristics that were predictive for long-term survival. The only predictors for better survival were treatment in earlier salvage (S1/S2 vs. S3+), and the ability to undergo consolidative HSCT. This highlights the unmet need for novel effective therapies for T-ALL that can induce MRD negative responses, and bridge patients to a potentially curative HSCT. Nonetheless, several promising therapeutic strategies are being evaluated in T-ALL. Preliminary results of the combination of venetoclax (selective inhibitor of BCL-2, anti-apoptotic protein upregulated in ALL) with lower-intensity chemotherapy in newly diagnosed older patients unfit for intensive chemotherapy are promising with CR and MRD negativity rates of 91% and 100%, respectively.3 Similarly, the combination of venetoclax with navitoclax, another BH3-mimetic that inhibits BCL-2 and BCL-XL, may also be particularly promising.4 In addition, based on pre-clinical data of high expression of CD38 in T-cells, daratumumab, an anti-CD38 human monoclonal antibody approved in multiple myeloma, has shown encouraging anti-leukemic activity in small case series of R/R T-ALL, and is currently being evaluated in a phase 2 clinical trial (NCT03384654).5 Allogeneic chimeric antigen receptor T-cell therapy against CD7, which is expressed in 95% of T-ALL, is another emerging novel therapy with early promising results.6 In conclusion, while current therapies for T-ALL remain unsatisfactory, further research, clinical trial enrollment, and multicenter collaborations are highly needed in order to improve outcomes. To our knowledge, the current study is the first to provide survival estimates of patients with R/R T-ALL or T-LBL treated with contemporary regimens. This information should help to guide prognostication in this setting and also provides a reference points for the development of novel therapies for this population of high unmet medical need. E. Jabbour: Research grants with Amgen, AbbVie, Spectrum, BMS, Takeda Oncology, Pfizer, and Adaptive. F. Ravandi: Honoraria/member advisory boards with BMS, Novartis, AbbVie and Amgen. M. Konopleva: Consulting/honoraria from AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji; research funding/clinical trials support: AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, Astra Zeneca, Forty-Seven; stock options/royalties: Reata Pharmaceutical. H. Kantarjian: Grants from AbbVie, Agios, Amgen, Ariad, Astex, BMS, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, and Pfizer. N.J. Short has served as consultant for Takeda Oncology and AstraZeneca, reports receiving commercial research grants from Takeda Oncology and Astellas Pharma Inc., and has received speakers’ bureau honoraria from Amgen. EJ conceived, designed, directed and supervised the study, and revised the manuscript. BS collected and analyzed the data, and wrote the manuscript draft. ASA analyzed the data and completed the figures. NJS critically reviewed and revised the manuscript. All authors read, revised and approved the final manuscript. Supplementary Figure 1 Schema of patient population. Among 82 patients with R/R T-cell ALL/LBL, 32 (39%) were in S1, 22 were in S2 (27%), and 28 were in S3+ (34%). Supplementary Table 1 Baseline characteristics of patients with R/R T-cell ALL/LBL at presentation in salvage Supplementary Table 2 Salvage therapies and outcome of patients with R/R T-cell ALL/LBL Supplementary Table 3 Univariate and multivariate analyses for overall survival of patients with R/R T-cell ALL/LBL Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.