Outcome after Relapse or Progression Following First Allogeneic Hematopoietic Stem Cell Transplantation in Children with Acute Leukemia. a Retrospective Analysis from the French Society of Bone Marrow Transplantation and Cell Therapies
Authors: Roux Clémence , Tifratene Karim , Raus Nicole , Socie Gerard , Galambrun Claire , Bertrand Yves , Rialland Fanny , Jubert Charlotte , Contet Audrey , Paillard Catherine , Sirvent Anne , Nelken Brigitte , Beguin Yves , Yakoub-Agha Ibrahim , Mohty Mohamad , Dalle Jean-Hugues , Michel Gerard , Pradier Christian , Peffault de Latour Regis , Rohrlich Pierre-Simon 
Published: November 2019

Abstract
Background
Hematopoietic stem cell transplantation (HSCT) has contributed to improve outcome for pediatric patients with acute leukemia (AL). However, post-transplantation relapse is still associated with a dismal prognosis and its optimal treatment remains unclear. Therapeutic strategies may vary according to the relapse delay, as well as centers and child's specific requirements.
Aim
We aimed to compare patients' related factors and treatment strategy, in case of relapse or progression post-allogeneic HSCT in children with acute leukemia in a recent ten-year period.
Methods
We analysed all consecutive 334 children (<18 years, 134 Females) who received a first allogeneic HSCT for ALL or AML from January 2000 to December 2009 and experienced a relapse or progression thereafter. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by the 33 centers of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) who participated to this study. The primary endpoint was overall survival (OS) after diagnosis of relapse or progression post first HSCT whatever the treatment post relapse was. Secondary endpoints included OS after a) second HSCT, b) chemotherapy alone, c) donor lymphocytes infusion (DLI) d) chemotherapy followed by DLI or e) supportive and palliative care. We also assessed prognostic risk factors for survival after failure post-HSCT.
Results
279 patients (110 females and 169 males) with a median age of 8.8 years at transplantation (range: 0.52-17.99) were included. Diseases were 149 ALL (B-cell phenotype, n=120; T-cell phenotype, n=29), 122 AML and 8 biphenotypic AL. At transplantation, 233 patients were in complete remission (CR) (CR1 n=121, CR2 n=94, CR3 n=18) while 46 had a cytologically detectable disease. Donors were matched related siblings (36%), mismatched related (4%), matched unrelated (18%), mismatched unrelated (24%), unrelated without precision (16%) or syngenic (2%). Stem cell source was bone marrow, peripheral stem cells, umbilical cord blood in 65%, 12%, 23% of cases, respectively. Median time from diagnosis to first HSCT was 263 days. 91% (n=254) children received myeloablative conditioning and 9% (n=25) received reduced intensity conditioning regimens. Total body irradiation (TBI) was performed in 153 children. Acute GVHD after first HSCT occurred in 157 patients (grade I n= 62 grade II to IV n= 94). The median delay from first HSCT to relapse/progression was 182 days. The treatments for relapse after first HSCT consisted in chemotherapy alone (n=103), chemotherapy followed by second HSCT (n=70), supportive and palliative care (n=66), combination of chemotherapy and DLI (n=27), or isolated reinfusion of donor lymphocytes (DLI) (n=13).
At the time of analysis 40 patients (12%) were alive with a median follow up of 1315 days (range 58;4182). The median OS duration after relapse was 149 days among the 334 patients. The median survival duration in days according to therapy was as follows [confidence interval]: DLI after chemotherapy = 407 [156;658], Second allograft: 391 [264;518], chemotherapy: 180 [121;239], DLI alone: 140 [10;270], Palliative care: 43 [33;53] (see Figure 1). A Cox model analysis on 260 patients with complete files showed the impact of the following factors on survival, when comparing to the best line of treatment, ie chemotherapy+DLI; treatment by chemotherapy alone (HR 2.05, p=.008), palliative care (HR=5,7, p<.001), first transplant performed in complete remission (HR= 1.57, p=.031). The time interval from transplantation to relapse was also associated with prognosis: when comparing to relapses occuring within the first 90 days, day 90-179, day 180-269, and >270 days yielded hazard ratios of respectively .549, .479 and .293 (p <.003).
There was no impact on outcome from the following variables: gender, age at transplant, leukemia subtype, type of conditioning, conditioning with TBI , GVHD occurrence after the first transplant, stem cell source.
Conclusion
Despite evident limitations due to the retrospective setting of our analysis, best treatment consisted in second transplantation or the combination of chemotherapy plus DLI, both yielded similar long-term results. Those results favor the use of immune based strategies when possible in this particular situation of relapse post-HSCT, which should be evaluated in prospective trials.
Figure 1 Figure 1.

Disclosures
Mohty: Gentium S.p.A./Jazz Pharmaceuticals Inc.: Honoraria, Research Funding.