Prognosis and treatment for pediatric patients who relapse following first allo-HSCT

Relapse following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a major concern when treating high-risk leukemias or myelodysplastic syndromes (MDS). The consensus for adults is that a second allo-HSCT is the most beneficial intervention for survival following relapse; however, data are lacking for pediatric age groups.¹ Additionally, there is uncertainty on which prognostic factors best predict eligibility for, and survival following, a second transplant. Such data could provide physicians with more accurate patient stratification to better guide treatment.¹

Akshay Sharma and colleagues aimed to provide clarity for pediatric patients, recently publishing their retrospective analysis in Bone Marrow Transplantation. The primary objective was to assess the association of prognostic factors and treatment options with post-relapse survival following allo-HSCT, in patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and MDS. The authors also investigated the association of prognostic factors with receiving a second transplant.¹ We summarize key findings below.

Study design

• A single-center retrospective analysis performed at St. Jude Children’s Research Hospital, with data collected between 1990 and 2018, within a pediatric cohort (≤21 years old).
• 703 patients met the inclusion criteria, and 221 patients relapsed following their first allo-HSCT and were included in the primary cohort for analysis.
• Median follow-up for the entire cohort was 1.6 years (range, 0–27.6) and for the survivors this was 10.1 years (range, 1–27.6).
• Patient characteristics that may affect survival or likelihood of receiving a second allo-HSCT are summarized in Table 1. 

Table 1. Patient characteristics for primary cohort*

ALL, acute lymphoblastic leukemia; allo-HSCT, allogeneic stem cell transplant; AML, acute myeloid leukemia; CR1, first complete remission; CR2+, second or subsequent complete remission; GvHD, graft-versus-host disease; MDS, myelodysplastic syndromes. *Data from Sharma et al.1
Characteristic	N = 221
≤10 years old, %	63.3
Sex, %               Female	43.0
Diagnosis, %               ALL               AML               MDS	37.6 55.7 6.8
CR status at first allo-HSCT, %               CR1               CR2+	28.1 29.4
Haploidentical donor, %	33.0
GvHD status, %               Acute GvHD (Grade 3–4)               Chronic GvHD	10.4 13.6
≤6 months to relapse, %	61.1
Year of relapse, %               1990–2000               2001–2010               2011–2018	29.0 40.3 30.7

Key findings

Prognostic factors and receiving a second allo-HSCT

Following univariate analysis, it was reported that being in complete remission at first allo-HSCT, relapse after 6 months, history of GvHD following first allo-HSCT, and relapse within 2011–2018, were all factors associated with increased likelihood of receiving a second transplant (Table 2).

Table 2. Association of prognostic factors and receiving a second allo-HSCT*

allo-HSCT, allogeneic stem cell transplantation; CI, confidence interval; CR1, first complete remission; CR2+, second or subsequent complete remission; GvHD, graft-versus-host disease; OR, odds ratio. *Data from Sharma et al.1
Prognostic factors	Univariate			Multivariable
	N = 221, n	2nd HSCT, %	p value	OR	95 % CI	p value
CR at first allo-HSCT               CR1               CR2+	62 65	41.9 23.1	0.02	1 0.5	0.2–1.3	0.26
Relapse-free duration               Relapse ≤6 months               Relapse >6 months	135 86	12.6 51.2	< 0.001	0.2 1	0.1–0.4	< 0.001
Chronic GvHD               Yes               No	30 191	46.7 24.6	0.01	1.7 1	0.6–4.5	0.33
Year of first relapse               1990–2000               2001–2010               2011–2018	61 87 73	9.8 27.6 42.5	< 0.001	0.1 0.5 1	0.02–0.3 0.2–1.0	< 0.001

As highlighted in Table 2, following multivariable analysis, only a longer duration of remission (>6 months) after allo-HSCT, and undergoing first allo-HSCT in a more recent time period (2011–2018), were significantly associated with receiving a second allo-HSCT.

Prognosis and treatment association with survival outcomes

Following univariate analysis, it was found that being female, in first complete remission, having relapse after 6 months of first allo-HSCT and/or relapse in a recent time period were factors significantly associated with improved post-relapse survival. In terms of treatment, receiving a second allo-HSCT or donor lymphocyte infusion were also associated with improved survival (Table 3).

Table 3. Association of prognostic factors and treatment options with 3-year overall survival*

HR, hazard ratio; DLI, donor lymphocyte infusion. *Data from Sharma et al.1
Prognostic factors	Post-relapse survival
	Univariate			Multivariable
	N = 221	Alive, %	p value	HR	95% CI	p value
Sex               Male               Female	126 95	7.1 16.8	0.04	0.8 1	0.6–1.1	0.22
CR at first allo-HSCT               CR1               CR2+	62 65	16.1 12.3	0.01	1 1.2	0.8–1.7	0.07
Relapse-free duration               Relapse ≤6 months               Relapse >6 months	135 86	5.2 20.9	< 0.001	4.6 1	3.2–6.7	< 0.001
Year of first relapse               1990–2000               2001–2010               2011–2018	61 87 73	3.3 8.0 21.9	< 0.001	2.6 1.6 1	1.7–3.9 1.1–2.2	< 0.001
Treatment post-relapse               2nd allo-HSCT               DLI               Chemotherapy/ supportive care	61 28 132	29.5 7.1 3.8	< 0.001	0.4 0.6 1	0.3–0.6 0.4–0.9	< 0.001

Following a multivariable analysis, the only factors significantly associated with improved post-relapse survival were duration from first allo-HSCT to relapse, receiving a second allo-HSCT or DLI, and relapse in a more recent time period (Table 3).

• Of these factors, duration of remission and receiving a second allo-HSCT were the strongest predictors of survival (p < 0.001).
• Sub-analysis combining these predictors revealed a second allo-HSCT led to improved OS regardless of time to relapse.

Conclusion

Overall, this study demonstrated the survival benefit of a second allo-HSCT following relapse for patients of pediatric age with AML, ALL, and MDS. However, it was observed that duration of post-transplant remission was associated with likelihood of a second transplant, thus reducing the number of patients eligible for this treatment benefit.

Importantly, the authors reported patients who relapsed less than 6 months after allo-HSCT but received a second transplant had comparable overall survival with those who relapsed after 6 months. As such, it may be beneficial to include patients for a second allo-HSCT irrespective of their remission status.