Abstract

Background

Arsenic trioxide (ATO) is regarded as the treatment of choice for relapsed PML-RARA+ acute promyelocytic leukemia (rAPL). In 2008, a European online registry of rAPL based on uniform CRFs was established under the auspices of the European LeukemiaNet (ELN) to gain insights in the clinical and biological characteristics of rAPL treated with ATO and to allow an assessment of the different options for postconsolidation therapy.

Methods

Eligibility criteria for prospective or retrospective registration were PML-RARA+ 1st or successive molecular or clinical relapse of APL from the year 2003 onwards. The treatment should be based on the European recommendations for treatment of rAPL (www.leukemia-net.org/content/), which offer induction and consolidation therapy with ATO and several options for post-consolidation therapy including autologous or allogeneic stem cell transplantation or chemotherapy consolidation followed by various modifications of maintenance therapy ± ATO - to be selected depending on several variables including patient age, performance status, PCR status after consolidation, type of frontline therapy, first CR duration and donor availability.

Results

By 30 June 2013, of 220 registered cases, 198 were evaluable (172 in 1st, 26 in ≥2nd relapse). Of these, 149 patients (pts) in 1st relapse received ATO-based salvage therapy after standard frontline therapy based on all-trans retinoic acid (ATRA) and anthracyclines (98 hematological (hematol) relapses of bone marrow combined with CNS relapse in 5 pts, 40 molecular (mol), 11 isolated extramedullary, mainly CNS). Clinical characteristics: median age at relapse 44 years (y) (4 to 81), 67% males, Sanz Risk Score at 1st diagnosis: low 23%, intermediate 48% and high 29% of pts. Median duration of first remission was 565 d (105 d to 7.0 y). The median treatment duration of ATO (0,15 mg/kg/day) plus ATRA (44% of pts) for remission induction (ind) was 30 days (d) and for consolidation (cons) 25 d. CNS relapses received ATO and additional intrathecal chemotherapy ± irradiation.

WBC

white blood cell count; Leuko.: leukocytosis requiring hydroxyurea; ADS: APL differentiation syndrome; 1 median; 2 hematological; 3 RT-PCR of PML-RARA negative.

In non-hematological relapses, no early deaths occurred and no major side effects of ATO were seen. Median follow up of the 149 pts was 2.8 y (6 d to 10 y). Three-year overall survival (OS) was 70%, 95%CI [61;79] and 6-year OS 56% [42;70]. Three-year OS of hematological, molecular and extramedullary relapse was 69% [58;80], 66% [48;84] and 90% [81;99], respectively (p=0.2). Concerning outcome after transplantation, 3-year OS after autologous was 82% [70;94] (n=55), after allogeneic 75% [58;92] (n=32) and without transplantation 66% [48;84] (n=55) (p=0.4).

Conclusions

With ATO-based salvage therapy over 50% of patients in 1st relapse of APL can probably be cured. Pts in molecular relapse have a lower rate of early complications and death. Long-term survival is possible with transplantation-free approaches, but transplantation seems to improve the outcome.

Table 1

Pretreatment parameters and adverse effects during ATO induction: Comparison of non-hematological (isolated extramedullary and molecular) vs. hematological relapse:

Relapse typeWBC1 (x109/L)Platelets1 (x109/L)Coagulo-pathy (%)Bleed-ing (%)Leuko.(%)ADS(%)
Non-hematol. 4.5 182 
Hematol. 3.2 58 25 24 40 28 
p-value 0.01 <0.0001 0.02 0.01 <0.0001 <0.0001 
Relapse typeWBC1 (x109/L)Platelets1 (x109/L)Coagulo-pathy (%)Bleed-ing (%)Leuko.(%)ADS(%)
Non-hematol. 4.5 182 
Hematol. 3.2 58 25 24 40 28 
p-value 0.01 <0.0001 0.02 0.01 <0.0001 <0.0001 
Table 2

Results after induction and consolidation therapy:

Relapse typeCR2(%)Early death (%)Resistance2 (%)Mol CR3after ind (%)Mol CR3after cons (%)
Extramedullary 100 
Molecular 51 72 
Hematological 89 50 81 
p-value 0.2 0.2 0.5 0.8 0.4 
Relapse typeCR2(%)Early death (%)Resistance2 (%)Mol CR3after ind (%)Mol CR3after cons (%)
Extramedullary 100 
Molecular 51 72 
Hematological 89 50 81 
p-value 0.2 0.2 0.5 0.8 0.4 
Disclosures:

Lengfelder:TEVA/ Cephalon: Research Funding. Lo-Coco:TEVA: Speakers Bureau.

Author notes

*

Asterisk with author names denotes non-ASH members.