MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL
Abstract
:Simple Summary
Abstract
1. Introduction
2. ALL in Adolescents and Young Adult Patients
2.1. AYA Patient Identification: Age Ranges
2.2. Ph− ALL: Diagnostic Subsets Defined by Immunophenotype and Cytogenetics/Genetics in AYAs
2.3. Treatment: Traditional Adult vs. Modern Pediatric Regimens
- Intensive chemotherapy regimens inspired to modern pediatric schedules and treatment principles are superior to historical adult-type programs, as demonstrated with very few exceptions by comparative analyses among successive Phase 2 trials and many large non-comparative trials [6,16,17]. Whenever available, retrospective comparisons with historical datasets (not shown in the table and available in study references) confirm an average improvement of outcome measures of 15–25%.
- In these modern AYA or AYA-containing adult ALL studies, the projected survival rates at 5 years (range 3–7 years), assuming “cure” for most patients who remain disease-free at ≥5 years, is 50% and greater (overall survival, OS), with age-related variations and OS rates of 60–70% and occasionally higher in younger age groups.
- Unlike OS, which reflects the cumulative survival effect of both first line and salvage therapies, relapse-free and event-free survival (RFS and EFS) depict the curative potential of upfront therapy only, in CR patients and all study patients, respectively. These figures range 55–70% (RFS) and 40–74% (EFS), once again with significantly better results in younger age groups.
- The overall chemotherapy intensity is increased in pediatric-based regimens, with regard to vincristine, corticosteroids, antimetabolites (cytarabine, methotrexate and 6-mercaptopurine), L-asparaginase and, more recently, Pegylated-asparaginase (Peg-ASP). Consequently, drug-related toxicity may be higher, requiring higher clinical skills for the management and prevention of toxic side effects.
- The improved pediatric-like protocol may consist of an unmodified or modified pediatric schedule, in the latter case adapting some treatment elements to an increasing patient age with attending risks of treatment toxicity. The issue of Peg-ASP dosing and toxicity is highly critical in patients at older age [52,53].
- The patients who achieve CR, namely about 90% of all patients (≥95% in younger age groups), are usually risk-stratified to assess the individual risk class and decide about the application of risk-specific treatments that range, for high-risk (HR) patients, from chemotherapy intensification to allogeneic hematopoietic cell transplantation (HCT) and/or experimental new agents. Most patients at standard-risk (SR) or intermediate-risk can achieve cure with a full chemotherapy regimen including maintenance as standard of care, without HCT, this lowering the incidence of non-lethal and lethal toxicities (10–15% average mortality from HCT).
- In the risk stratification process, by analogy with pediatric trials, the analysis of post-induction MRD is crucial since it has been demonstrated to be the most powerful predictive factor for marrow relapse in multivariable analysis from several studies [7,8,9,10]. Therefore, MRD is currently used together with other risk factors for the definition of risk groups and individual risk profiles.
3. Methods of MRD Assessment
3.1. Multiparameter Flow Cytometry
3.2. PCR for Fusion Genes and Transcripts
3.3. PCR for Ig and TCR Gene Rearrangements
3.4. Next Generation Sequencing
3.5. Digital Droplet PCR
4. MRD in AYA Ph− ALL
4.1. MRD Study Results for Risk Stratification
Trial/Study (Ref.) | Patient Age (Years), Median (Range) | MRD Analysis | Favorable MRD Response | Comparative Outcomes: Favorable MRD Cut-Offs Vs. Not | ||
---|---|---|---|---|---|---|
Evaluable/CR, No. (%) | Method 1 | Cut-Off 2 | No. (%) | |||
AYA only (maximum age 40 years) | ||||||
MRC-UKALL2003 [11] | NR (16–24) | 223/229 (97) | Mol | Negative/<0.01% d29, negative at EOC | 54 (24) | 5-y EFS 93% vs. 63–71% (p = 0.0001) 3 |
PETHEMA ALL08 [35] | 20 (15–30) | 61/68 (90) | MFC | <0.1% w5–6, <0.05% w19–20 | 48 (77) | NR |
GIMEMA LAL1308 [39] | NR (18–35) | 64/68 (94)/ 66/68 (97) 49/68 (72)/ 50/68 (73) | MFC Mol | <0.1% d33/78 | 37 (58)/54 (82) 28 (57)/38 (76) | 4-y OS by d33 MRD 67–75% vs. 27–41% (p = 0.002) 4 4-y RFS by d33 MRD 67–73% vs. 27–43% (p ≤ 0.025) 4 4-y OS by d78 MRD 74–77% vs. 31–39% (p ≤ 0.01) 4 4-y RFS by d78 MRD 71–72% vs. 26–34% (p ≤ 0.01) 4 |
MDACC (aBFM/HyperCVAD) * [36] | 22 (13–39) | 93/199 (47) | MFC | <0.01% d29/d84 | 58 (62) | 5-y OS by d29 MRD 75% vs. 40% (p = 0.004) 5-y OS by d84 MRD 75% vs. 22% (p = 0.0004) |
CALGB 10,403 [37] | 24 (17–39) | 80/237 (34) | Mol | Negative at EOI | 35 (44) | 3-y RFS 85% vs. 54% (p = 0.0006) |
AYA and adults (maximum age > 40 years) | ||||||
NOPHO 2008 [14] | 26 (18–45) | NR/218 | Mol | <0.1% d29/d79 | (56–64) 5 | NR |
GRAALL 2003–2005 [26] | 31 (15–59) | 423/860 (49) | Mol | Negative/<0.01% w6 | 265 (63) | 5-y CIR 23–31% vs. 60% (p ≤ 0.01) |
GMALL 07/03 [74] | 34 (16–65) | 1057/1857 (57) | Mol | Negative w16 | 625 (59) | 5-y OS 83% vs. 43–68% (p < 0.0001) 6 |
MDACC [75] | 37 (15–86) | 215/394 (55) | MFC | <0.01% d24/d108 | 147 (68)/194 (90) | 3-y OS by d24 MRD 76% vs. 49–61% (p = 0.001) 7 3-y EFS by d24 MRD 65% vs.16–46% (p < 0.001) 7 |
PETHEMA ALL-HR11 [49] | 40 (15–60) | 286/289 (99) | MFC | <0.1% w5–6 | 220 (82) | 5-y OS 59% vs. 38% (p < 0.001) |
NILG 10/07 [51] | 41 (18–65) | 109/140 (78) | Mol | <0.01% w10–16/negative w22 | 68 (62) | 5-y OS 78% vs. 34% (p < 0.0001) 5-y RFS 66% vs. 29% (p < 0.0001) |
HOVON-100 ** [41] | 42 (18–70) | 168/297 (56) | Mol/MFC | <0.01% after consolidation 1 | 126 (75) | NR |
4.2. Terminology of MRD Response for Clinical Purposes
4.3. MRD-Related Outcomes
4.4. Risk of Relapse in MRD Responders
4.5. Allogeneic HCT for MRD Positive States
4.5.1. Allogeneic HCT Results in MRDpos AYA Ph− ALL
Trial/Study (Ref.) | MRD+ and/or HR Patients Eligible to HCT/HR Protocol (No.) | Had Allogeneic HCT/HR Protocol (No.) | Outcomes * |
---|---|---|---|
AYA only (maximum age 40 years) | |||
PETHEMA ALL08 [35] | 2 MRDpos and 20 HR to HCT or HR protocol | 5 HCT and 13 HR protocol | 4 HCT survivors (80%) and 7 HR protocol survivors (54%) |
MRC-UKALL2003 [11] | 109 MRDpos to random study and 14 HR to HCT 1 | 64 randomized and 14 HCT | 9 HCT survivors (64%) |
MDACC [76] | 17 MRDpos or HR to HCT | 17 HCT | 7 survivors (41%), 5 in CR (29%) |
CALGB 10,403 [37] | 20 HR/other 2 to HCT | 20 HCT | 8 survivors (40%) |
GIMEMA LAL1308 [40] | 21 MRDpos to HCT and 9 HR to HR protocol | 15 HCT and 12 HR protocol | 4-y OS HR 52.6% vs. SR 73.4% (p = 0.032) 4-y RFS HR 54.2% vs. SR 66.6% (p = 0.51) |
AYA and adults (maximum age > 40 years) | |||
NOPHO 2008 [14] | 35 MRDpos to HCT and 45 HR to HR protocol | NR | 5-y EFS 61% 3 |
GRAALL 2003–2005 [83] | 105 HR MRDpos to HCT | 59 HCT | 3-y OS 65% vs. 40% (p = 0.001) 3-y RFS 56% vs. 22% (p = 0.002) |
GMALL 07/03 [74] | 196 MRDpos to HCT | 121 HCT | 5-y OS 53% vs. 28% (p < 0.0001) 5-y CRD 56% vs. 9% (p < 0.0001) |
PETHEMA ALL-HR11 [49] | 66 MRDpos and 40 HR to HCT | 62 HCT | 5-y OS 54% (as treated) |
NILG 10/07 [51] | 41 MRDpos to HCT | 23 HCT | 5-y OS 35% vs. 14% (p = 0.02) 5-y OS RFS 43% vs. 12% (p = 0.09) |
4.5.2. Pre-Transplantation MRD Status
5. New Therapeutic Options for MRD Positive ALL
5.1. Immunotherapy for BCP ALL
5.1.1. Blinatumomab
5.1.2. Inotuzumab Ozogamicin
5.2. Chimeric Antigen Receptor-Modified T-Cell Therapy
5.3. Investigational Agents for T-ALL
5.3.1. Nelarabine for MRDpos T-ALL
5.3.2. Immunotherapy for MRDpos T-ALL
5.4. Other Experimental Approaches
5.4.1. Molecular Profiling for Precision Medicine
- Most relevant is Ph-like ALL, which is rather frequent in AYA patients and carries a higher risk of MRD persistence. Some of the associated gene abnormalities recognizable in this poor risk entity (ABL-class fusions, CLRF2 deregulation and JAK/STAT and IL7R pathway alterations, among others) are actionable by TK inhibitors, JAK inhibitors (ruxolitinib) and other similar drugs. Trials in children, AYA and adults have been incepted worldwide, sometimes with promising preliminary results [126,127,128,129]. The data from these studies may elucidate which of these new drugs or drug combinations with either chemotherapy, immunotherapy and/or other targeting agents could optimize the outcome of the distinct genetically defined Ph-like ALL subsets.
- Among the BCP ALL subsets to consider for targeted therapy is t (v;11) + ALL or ALL carrying KMT2A gene rearrangements, most frequently t (4;11) + ALL. This entity stands out for its clinical aggressiveness. In this subset, the available molecular studies point to a therapeutic use of BCL-2 inhibitors (venetoclax and navitoclax) and DOT-L1 and histone-deacetylase inhibitors; however, the relative rarity of this ALL syndrome precludes an extensive clinical evaluation of these drugs outside large collaborative clinical trials.
- There are many more candidates for targeted therapy of BCP ALL subsets or ALL in general, as extensively reviewed [122]. Most of these drugs are under investigation in early clinical trials, and it is too early to define exactly their place and/or anticipate their approval for use as standard agents for front-line therapy and/or MRDpos conditions. Worthy of mentioning are the proteasome inhibitors, again the BCL-2 inhibitors and the activators of P53-mediated apoptosis, given the frequent dysregulation of these molecular mechanisms. Likewise, the analysis of bone marrow immune cell contexture led to identify a poor risk ALL subset with PD1 + TIM3 + CD4 + bone marrow T-cells > 0.1% that might be targeted by PD1 checkpoint inhibitors [130].
- Many of the new drugs potentially active in BCP ALL could be exploited in T-ALL as well, namely inhibitors of the antiapoptotic BCL-2 family members and inhibitors of JAK/STAT, PI3K/Akt/mTOR, MAPK and Notch-1, the latter being a typical T-ALL target. While experience with Notch-1 inhibitors has been rather disappointing so far, BCL-2 inhibitors navitoclax and venetoclax induced a CR in six of 16 patients with refractory T-ALL, achieving undetectable MRD in four [129]. ETP ALL may be sensitive to the JAK-2 inhibitor ruxolitinib.
5.4.2. Drug Sensitivity Profiling for Precision Medicine
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
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ALL Subset | Prognostic Category | Genetic/Cytogenetic Abnormality | Children (<15 Years) | AYA (15–40 Years) | Older Adults (>40 Years) |
---|---|---|---|---|---|
Ph− | Favorable | High hyperdiploidy | 20–25% | 5% | <5% |
t(12;21)/ETV6-RUNX1 | 25% | <5% | 1% | ||
Intermediate | Normal Karyotype | 10% | - | - | |
t(1;19)/TCF3-PBX1 | 5% | <5% | 1% | ||
Unfavorable | Low hypodiploidy, | 1% | 5% | >10% | |
t(v;11)/KMT2A+ | 6% | 4% | 15% | ||
Ph−like | 10–15% | 25–30% | 20% | ||
Ph+ | Unfavorable * | t(9;22)/BCR-ABL1 | 2% | 6% | 25% |
Age Groups and Trials (Ref.) | Patient Age (Years), Median (Range) | No. of Patients | Outcome Estimates (y, Years) | OS (%) | RFS (%) | EFS (%) |
---|---|---|---|---|---|---|
Maximum age ≤ 25 years | ||||||
FRALLE-93 1 [30] | 15.9 (15–20) | 77 | 5-y | 78 | 72 | 67 |
CCG 1882/191 1 [31] | 16 (16–20) | 197 | 7-y | 67 | - | 63 |
JALSG ALL202-U [32] | 19 (15–24) | 139 | 5-y | 73 | 67 | - |
CCG 19,61 1 [33] | (16–21) | 262 | 5-y | 78 | - | 72 |
MRC UKALL 2003 [11] | (16–24) | 229 | 5-y | 76 | - | 72 |
Maximum age ≤ 40 years | ||||||
PETHEMA ALL-96 [34] | 20 (15–30) | 81 | 6-y | 69 | - | 61 |
PETHEMA ALLRE08 [35] | 20 (15–30) | 66 | 5-y | 74 | - | - |
MDACC (augmented BFM) * [36] | 22 (13–39) | 106 | 5-y | 60 | - | - |
CALGB 10,403 [37] | 24 (17–39) | 295 | 3-y | 73 | 66 | 59 |
FRALLE 2000-BT [38] | (15–29) | 89 | 5-y | 66 | - | 61 |
GMALL 07/03 [39] | (15–35) | 887 | 5-y | 65 | 61 | - |
GIMEMA LAL1308 [40] | (18–35) | 76 | 4-y | 60 | 60 | - |
HOVON-100 1 [41] | (18–40) | 159 | 5-y | 60–56 2 | 58 | 61–64 2 |
Maximum age ≤ 55 years | ||||||
NOPHO ALL2008 [14] | 26 (18–45) | 221 | 5-y | 78 | - | - |
DFCI 01–175 1 [42] | 28 (18–50) | 92 | 4-y | 67 | 69 | 69 |
DFCI 06–254 1 [43] | 32 (18–50) | 89 | 3-y | 75 | 73 | 73 |
GMALL 07/03 [44] | 35 (15–55) | 1226 | 3-y | 60–67 3 | - | - |
Maximum age > 55 years | ||||||
RALL 2009 [45] | 30 (15–60) | 250 | 4-y | 66 | 69 | - |
GRAALL-2003 [46] | 31 (15–60) | 225 | 3.5-y | 60 | 59 | 55 |
GRAALL-2005 [47] | 36 (18–59) | 787 | 5-y | 59 | - | 52 |
Toronto (DFCI 91–01) [48] | 37 (18–60) | 85 | 5-y | 63 | 71 | - |
PETHEMA ALL-HR-11 [49] | 40 (15–60) | 348 | 5-y | 49 | - | 40 |
JALSG ALL 202-O [50] | 40 (24–65) | 115 | 5-y | 64 | 58 | - |
NILG 10/07 4 [51] | 41 (18–65) | 161 | 5-y | 52 | 53 | 46 |
Study Group | MRD | Genetics | WBC | Miscellaneous |
---|---|---|---|---|
RALL | + | KMT2A+, t(1;19) | - | Age > 30 |
GMALL | + | KMT2A+ | >30 (B) | Late CR, proB, early/mature-T |
HOVON | + | adverse | >30 (B), >100 (T) | Late CR |
PALG | + | KMT2A+ | >30 (B), >100 (T) | CNS+ |
FALL | + | Abn11q, hypodiploid | >100 | Late CR, D15 BM blasts > 25% |
GIMEMA | + | adverse | >100 | Early/mature-T |
UKALL | + | adverse | High counts | - |
SVALL | + | KMT2A+, hypodiploidy | - | EOI BM blasts > 5% |
CELL | + | - | - | - |
PETHEMA | + | - | - | - |
GRAALL | + | - | - | - |
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Tosi, M.; Spinelli, O.; Leoncin, M.; Cavagna, R.; Pavoni, C.; Lussana, F.; Intermesoli, T.; Frison, L.; Perali, G.; Carobolante, F.; et al. MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL. Cancers 2021, 13, 2108. https://doi.org/10.3390/cancers13092108
Tosi M, Spinelli O, Leoncin M, Cavagna R, Pavoni C, Lussana F, Intermesoli T, Frison L, Perali G, Carobolante F, et al. MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL. Cancers. 2021; 13(9):2108. https://doi.org/10.3390/cancers13092108
Chicago/Turabian StyleTosi, Manuela, Orietta Spinelli, Matteo Leoncin, Roberta Cavagna, Chiara Pavoni, Federico Lussana, Tamara Intermesoli, Luca Frison, Giulia Perali, Francesca Carobolante, and et al. 2021. "MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL" Cancers 13, no. 9: 2108. https://doi.org/10.3390/cancers13092108