Relevance of flow cytometric categorization and end-of-induction measurable residual disease assessment in pediatric and adult T-lymphoblastic leukemia patients

Karthik Bommannan; Jhansi Rani Arumugam; Venkatraman Radhakrishnan; Jayachandran Perumal Kalaiyarasi; Parathan Karunakaran; Nikita Mehra; Tenali Gnana Sagar; Shirley Sundersingh

doi:10.5045/br.2022.2022104

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Blood Res 2022; 57(3):

Published online September 30, 2022

https://doi.org/10.5045/br.2022.2022104

Relevance of flow cytometric categorization and end-of-induction measurable residual disease assessment in pediatric and adult T-lymphoblastic leukemia patients

Karthik Bommannan¹, Jhansi Rani Arumugam¹, Venkatraman Radhakrishnan², Jayachandran Perumal Kalaiyarasi², Parathan Karunakaran², Nikita Mehra², Tenali Gnana Sagar², Shirley Sundersingh¹

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Departments of ¹Oncopathology and ²Medical Oncology, Cancer Institute (W.I.A.), Adyar, India

Correspondence to : Karthik Bommannan, M.D., D.M.
Department of Oncopathology, Cancer Institute (W.I.A), Adyar, Chennai 600020, India
E-mail: bkkb87@gmail.com

*This study was supported by a grant from Indian Council of Medical Research (ICMR) and the Indian Childhood Collaborative Leukemia (ICiCLe) project of the National Cancer Grid (NCG).

Received: May 16, 2022; Revised: June 15, 2022; Accepted: June 21, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

Background
T-lymphoblastic leukemia (T-ALL) patients expressing myeloid/stem cell antigens are classified as early T-cell precursor lymphoblastic leukemia (ETP-ALL) or near-ETP-ALL.
Methods
Clinico-laboratory profiles, flow cytometric end-of-induction measurable residual disease (EOI-MRD), and survival of treatment naïve T-ALL patients were analyzed according to their immunophenotypic subtypes.
Results
Among 81 consecutive T-ALL patients diagnosed, 21% (N=17) were ETP-ALL and 19% (N=15) were near-ETP-ALL. EOI-MRD was detectable in 39% of the 59 samples tested (31.6% of pediatric samples and 52.4% of adult samples). The frequency of EOI-MRD positivity was significantly higher among ETP-ALL (75%, P=0.001) and near-ETP-ALL (71%, P=0.009) patients compared to that in conventional-T-ALL (con-T-ALL) patients (22.5%). CD8 (P=0.046) and CD38 (P=0.046) expressions were significantly upregulated in the EOI blasts of con-T-ALL and ETP-ALL samples, respectively. The 2-year rates of overall (OS), relapse-free (RFS), and event-free survival (EFS) among the T-ALL patients (pediatric vs. adult) was 79.5% vs. 39.8% (P<0.001), 84.3% vs. 60.4% (P=0.026), and 80.3% vs. 38% (P<0.001), respectively. Univariate analysis revealed that 2-year EFS and RFS of pediatric T-ALL patients was independent of T-ALL subtype and was influenced only by EOI-MRD status. However, 2-year OS, RFS, and EFS among adult T-ALL patients were EOI-MRD independent and influenced only by the near-ETP-ALL phenotype.
Conclusion
Two-year survival among pediatric and adult T-ALL patients is attributed to EOI-MRD status and near-ETP-ALL phenotype, respectively.

Keywords Measurable residual disease, Flow cytometry, T-lineage acute lymphoblastic leuke mia, ETP-ALL, Near-ETP-ALL

Article

Original Article

Blood Res 2022; 57(3): 175-196

Published online September 30, 2022 https://doi.org/10.5045/br.2022.2022104

Relevance of flow cytometric categorization and end-of-induction measurable residual disease assessment in pediatric and adult T-lymphoblastic leukemia patients

Karthik Bommannan¹, Jhansi Rani Arumugam¹, Venkatraman Radhakrishnan², Jayachandran Perumal Kalaiyarasi², Parathan Karunakaran², Nikita Mehra², Tenali Gnana Sagar², Shirley Sundersingh¹

Departments of ¹Oncopathology and ²Medical Oncology, Cancer Institute (W.I.A.), Adyar, India

Correspondence to:Karthik Bommannan, M.D., D.M.
Department of Oncopathology, Cancer Institute (W.I.A), Adyar, Chennai 600020, India
E-mail: bkkb87@gmail.com

*This study was supported by a grant from Indian Council of Medical Research (ICMR) and the Indian Childhood Collaborative Leukemia (ICiCLe) project of the National Cancer Grid (NCG).

Received: May 16, 2022; Revised: June 15, 2022; Accepted: June 21, 2022

Abstract

Keywords: Measurable residual disease, Flow cytometry, T-lineage acute lymphoblastic leuke mia, ETP-ALL, Near-ETP-ALL

Abstract

Fig 1.

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Figure 1.Percentage of patients expressing lineage-specific and non-specific antigens across the immunophenotypic subtypes of T-ALL.

Blood Research 2022; 57: 175-196https://doi.org/10.5045/br.2022.2022104

Fig 2.

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Figure 2.Two-year overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) across all immunophenotypic subcategories of T-ALL analyzed together among all age groups (first row), pediatric patients (second row), and adult patients (third row).

Blood Research 2022; 57: 175-196https://doi.org/10.5045/br.2022.2022104

Table 1 . Clinical and laboratory characteristics of T-ALL subcategories..

Parameters	Overall T-ALL (N=81)	T-ALL subcategories			P
Parameters	Overall T-ALL (N=81)	Con-T-ALL (N=49)	ETP-ALL (N=17)	Near-ETP-ALL (N=15)	ETP-ALL vs. Near-ETP-ALL	ETP-ALL vs. Con-T-ALL	Near-ETP-ALL vs. Con-T-ALL
Median (range) age in years	17 (1–52)	15 (1–50)	17 (13–39)	23 (5–52)	0.882	0.003	0.016
Age group					1.000	0.039	0.040
Pediatric (%)	47 (58)	34 (72%)	7 (15%)	6 (13%)
Adult (%)	34 (42)	15 (44%)	10 (29%)	9 (27%)
Sex (male:female)	3.8:1	4.4:1	3.2:1	2.7:1	1.000	0.645	0.485
Median (range) Hb in g/L	90 (30–142)	90 (30–142)	92 (30–131)	88 (41–133)	0.737	1.000	0.751
Median (range) WBC count, ×10⁹/L	64.1 (1–850)	173 (1.1–850)	70 (1–480)	145 (3–590)	0.049	0.005	0.751
Median (range) platelet, ×10⁹/L	54 (20–380)	73 (20–366)	125 (30–290)	127 (20–380)	0.911	0.008	0.080
Median (range) BM blast, %	87 (22–99)	87 (23–97)	86 (22–98)	89 (50–99)	0.473	0.795	0.663
Median (range) PB blast, %	78 (2–99)	80 (2–97)	42 (2–98)	83 (2–99)	0.193	0.174	0.411
Hyperleukocytosis	41%	45%	18%	53%	0.034	0.046	0.567
Hepatomegaly	42%	42%	27%	58%	0.204	0.283	0.319
Splenomegaly	56%	56%	47%	67%	0.516	0.550	0.489
Lymphadenopathy	78%	73%	87%	86%	1.000	0.290	0.342
Mediastinal mass	31%	36%	33%	13%	0.388	0.842	0.095
CNS involvement at diagnosis	3.2%	2 (5)	0%	0%	-	0.417	0.499
D8BNC	35%	32%	54%	20%	0.223	0.168	0.440
EOI-MRD positive	39% (N=59)	22.5% (N=40)	75%(N=12)	71.4% (N=7)	0.865	0.001	0.009
Relapse	20% (N=60)	18% (N=40)	17% (N=12)	38% (N=8)	0.292	0.947	0.204
OS at 24 months	65.2% (N=66)	70.6% (N=42)	60.4% (N=13)	52% (N=11)	0.180	0.551	0.019
RFS at 24 months	76.1% (N=60)	80% (N=40)	79% (N=12)	54.7% (N=8)	0.292	0.956	0.190
EFS at 24 months	64.5% (N=66)	70.3% (N=42)	66.6% (N=13)	41% (N=11)	0.076	0.978	0.013

Abbreviations: BM, bone marrow; CNS, central nervous system; D8BNC, day 8 blast not cleared; EFS, event-free survival; EOI-MRD, end-of-induction-measurable residual disease; Hb, hemoglobin; N, number of patients analyzed; NA, not applicable; OS, overall survival; PB, peripheral blood; RFS, relapse-free survival; WBC, white blood cells..

Table 2 . Clinical and laboratory characteristics of immunophenotypic T-ALL subcategories among pediatric and adult age groups..

Parameters	Pediatric patients						Adult patients
	T-ALL subtype			P			T-ALL subtype			P
	Con-T-ALL (N=34)	ETP-ALL (N=7)	Near-ETP-ALL (N=6)	ETP-ALL vs. Near- ETP-ALL	ETP-ALL vs. Con-T-ALL	Near- ETP-ALL vs. Con-T- T-ALL	Con-T-ALL (N=15)	ETP-ALL (N=10)	Near-ETP-ALL (N=9)	ETP-ALL vs. Near- ETP-ALL	ETP-ALL vs. Con- T-ALL	Near- ETP-ALL vs. Con-T-ALL
Median age (range) in years	12 (1–18)	16 (13–17)	13 (5–18)	0.295	0.056	0.343	25 (20–50)	34 (19–39)	29 (20–52)	0.842	0.367	0.290
Sex (male:female)	3.8:1	6:1	5:1	0.906	0.307	0.825	6.5:1	2.3:1	2:1	0.876	0.702	0.243
Median (range) Hb in g/L	91 (30–141)	97 (30–131)	83 (41–129)	0.181	0.465	0.517	89 (63–142)	80 (61–128)	88 (69–133)	0.356	0.338	1.000
Median (range) WBC, ×10⁹/L	110 (1.9–850)	90.4 (3.2–267)	244 (3–590)	0.366	0.198	0.810	88 (1.1–349)	55 (1–480)	68 (3.6–131)	0.017	0.036	0.682
Median (range) platelet, ×10⁹/L	83 (22–366)	125 (30–245)	149 (32–380)	0.731	0.175	0.240	52 (20–119)	125 (30–290)	100 (20–218)	0.720	0.016	0.138
Median (range) BM blast, %	87 (23–97)	86 (22–98)	95 (89–99)	0.149	0.845	0.029	87 (64–96)	85 (38–95)	76 (50–97)	0.863	0.770	0.446
Median (range) PB blast, %	84 (2–96)	86 (2–98)	98 (2–99)	0.268	0.883	0.074	61 (3–97)	36 (5–94)	76 (5–91)	0.161	0.073	0.770
Hyperleukocytosis	53%	29%	67%	0.089	0.240	0.533	27%	10%	44%	0.089	0.307	0.371
Hepatomegaly	45%	40%	67%	0.109	0.829	0.478	36%	20%	56%	0.109	0.404	0.349
Splenomegaly	61.3%	40%	67&	0.463	0.370	0.855	43%	50%	67%	0.463	0.729	0.265
Lymphadenopathy	75%	100%	100%	0.906	0.207	0.207	70%	80%	78%	0.906	0.560	0.658
Mediastinal mass	40%	20%	17%	0.153	0.402	0.286	29%	40%	11%	0.153	0.558	0.322
CNS involvement	4%	0%	0%	NA	0.638	0.638	8%	0%	0%	NA	0.452	0.620
Induction death	7%	0%	0%	0.098	0.508	0.508	0%	14%	60%	0.098	0.162	0.002
Induction failure	0%	0%	0%	NA	NA	NA	0%	17%	75%	0.065	0.001	0.001
D8BNC	30%	50%	50%	0.105	0.343	0.422	40%	57%	0%	0.105	0.486	0.074
EOI-MRD positive	15% (N=27)	83% (N=6)	60% (N=5)	0.346	0.001	0.025	38.5% (N=13)	67% (N=6)	100% (N=2)	0.346	0.252	0.104
Relapse	11% (N=27)	17% (N=6)	17% (N=6)	1.000	0.706	0.706	31% (N=13)	17% (N=6)	100% (N=2)	0.035	0.278	0.278
OS at 24 months	79% (N=29)	67% (N=6)	100% (N=6)	0.564	0.820	0.297	48% (N=13)	51% (N=7)	0% (N=5)	0.025	0.588	0.001
RFS at 24 months	87% (N=27)	83% (N=6)	75% (N=6)	0.937	0.805	0.720	64% (N=13)	75% (N=6)	0% (N=2)	0.012	0.705	0.014
EFS at 24 months	81% (N=29)	80% (N=6)	75% (N=6)	0.937	0.878	0.943	45% (N=13)	54% (N=7)	0% (N=5)	0.019	0.767	<0.001

Abbreviations: BM, bone marrow; CNS, the central nervous system; D8BNC, day 8 blast not cleared; EFS, event-free survival; EOI-MRD, end-of-induction-measurable residual disease; Hb, hemoglobin; N, number of patients analyzed; NA, not applicable; OS, overall survival; PB, peripheral blood; RFS, relapse-free survival; WBC, white blood cells..

Table 3 . Univariate analysis of covariates with event-free, relapse-free, and overall survivals..

	Variables	2 years-EFS			2 years-RFS			2 years-OS
	Variables	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P
Pediatric univariate	D8BNC	0.656	0.119–3.620	0.629	0.816	0.135–4.924	0.825	0.311	0.035–2.801	0.298
	Mediastinal mass	1.849	0.358–9.549	0.463	3.109	0.347–27.843	0.311	1.578	0.285–8.721	0.601
	Hyper-leucocytosis	0.422	0.082–2.179	0.303	0.693	0.116–4.154	0.688	0.228	0.027–1.951	0.117
	EOI-MRD positive	10.153	1.132–91.096	0.038	10.081	1.123–90.495	0.039	7.381	0.757–71.952	0.085
	Con T-ALL subtype	1.129	0.219–5.821	0.885	0.701	0.117–4.197	0.698	2.272	0.265–19.490	0.454
	ETP-ALL subtype	0.887	0.103–7.132	0.887	1.227	0.137–10.984	0.855	0.932	0.108–8.014	0.949
	Near-ETP-ALL subtype	0.956	0.115–7.947	0.967	1.425	0.159–12.757	0.762	0.780	0.091–6.700	0.821
Adult univariate	D8BNC	1.166	0.326–4.172	0.814	0.448	0.046–4.336	0.488	1.456	0.388–5.462	0.577
	Mediastinal mass	3.000	0.782–11.502	0.109	2.210	0.426–11.462	0.311	5.008	1.029–24.374	0.056
	Hyper-leucocytosis	1.784	0.615–5.178	0.287	4.084	0.908–18.368	0.067	1.482	0.483–4.547	0.491
	EOI-MRD positive	1.648	0.461–5.883	0.442	1.302	0.291–5.828	0.730	2.024	0.501–8.185	0.323
	Con-T-ALL subtype	0.425	0.144–1.253	0.121	0.607	0.135–2.738	0.516	0.361	0.117–1.117	0.077
	ETP-ALL subtype	0.730	0.203–2.623	0.630	0.461	0.055–3.833	0.473	0.824	0.226–3.002	0.769
	Near-ETP-ALL subtype	7.995	2.000–31.968	0.003	11.122	1.533–80.719	0.017	6.649	1.891–23.383	0.003

Abbreviations: CI, confidence interval; D8BNC, day 8 blast not cleared; EFS, event-free survival; EOI-MRD, end-of-induction-measurable residual disease; HR, hazard ratio; OS, overall survival; PB, peripheral blood; RFS, relapse-free survival..