Early Complications Of APL Treatment

History

A 54-year-old male came to the emergency room for a two-week history of fatigue, petechiae, and epistaxis. Patient medical history disclosed diabetes type II, hypercholesterolemia, and hypertension in pharmacological therapy.

Initial evaluation

At initial evaluation, skin examination revealed diffuse petechiae were evident predominantly on the lower extremities, but also on the torso and upper extremities. Lymphadenopathies and splenomegaly were absent. Vital signs were normal except from mild hypothension (90/60 mmHg).

Laboratory results

CBC, coagulation, and biochemistry tests were ordered and are shown in Table 1 below.

The complete blood count with differential revealed leukopenia anemia, and thrombocytopenia The D-dimer was significantly increased, and the patient’s fibrinogen was decreased with a normal ATIII value.

Bone marrow and cytogenetic observations

Urgent hematology consultation was requested and bone marrow examination was performed and morphologic examination showed infiltration by atypical promyelocytes with cytoplasm steeped with granules and occasional Auer rods. Upon morphologic suspect of APL, the hematology consultant strated therapy with all-trans retinoic acid (ATRA). Results of genetic and molecular analysis are shown in Table 2 below.

Indirect immunofluorescence with PGM3 (anti-PML) antibody showed a microspeckled pattern, typical of APL, and this was concordant with RT-PCR that showed positive for PML-RARA transcript (bcr1). ^1–2

A genetic diagnosis of PML/RARA positive acute promyelocytic leukemia was therefore established.

Treatment

Based on the initial WBC and platelet counts the patient was considered intermediate risk APL and treatment with ATO (0.15mg/kg/day) plus ATRA (45 mg/m2/day) was started.

After four days of therapy, the patient experienced weight gain from 79 kg to 84 kg with edema of the lower extremities, fever and developed respiratory insufficiency initially requiring only oxygen support and afterwards non-invasive mechanical ventilation. Chest X-ray was performed and the result are shown in Figure 2.

Therapy with Dexamethasone 10 mg twice a day was immediately started at onset of repiratory symptoms and ATRA and ATO temporarily discontinued.

Figure 2. Results of the chest X-ray

Diagnosis

The occurrence of increase in body weight (>5 kg), peripheral edema and respiratory failure is highly suggetive of of Differentiation Syndrome (DS). In addition, another important evidence is the presence of diffuse bilateral pulmonary infiltrates at the Chest X-ray, typical of Differentiation Syndrome clinical picture. Based on the criteria proposed by Montesinos et al.³, our syndrome was scored as a SEVERE. The clinical criteria are reported in Table 3 below.

Education comment

Differentiation syndrome (DS) is a relatively common and potentially severe complication that can occur in the first days from the beginning of ATRA and/or ATO therapy. Previously known as ATRA syndrome, this is characterized by several signs and symptoms including dyspnea with typical interstitial pulmonary infiltrates, unexplained fever, weight gain (> 5 kg), pleuro-pericardial effusion, unexplained hypotension, acute renal failure and peripheral edema. Frankel et al. initially described the syndrome as “definitely” present when 4 of the above mentioned signs or symptoms were detected and as indeterminate when in presence of < 4 signs or symptoms⁴. More recently, the PETHEMA group revised the DS grading and divided patients in those with severe DS (>3 signs or symptoms) and moderate DS (2-3 sign or symptoms)³. The incidence of DS is higher in the first week from the start of differentiation therapy, but a peak has also been reported in the third week of induction therapy.

In order to prevent the occurrence of this complication, steroid prophylaxis is generally recommended during induction therapy; however, different types of steroids and different duration of prophylaxis, have been employed by international cooperative groups. Particular attention should be always be reserved to patients with high-risk APL (WBC > 10×10⁹/L) and those with increased body mass index (BMI) throughout induction therapy for their increased probability of developing differentiation syndrome⁵–³. What is universally recommended is to initiate treatment with steroids (i.v. dexamethasone 10 mg twice a day) upon the earliest clinical suspicion of DS; ATRA and/or ATO treatment should generally be discontinued only in case of severe DS. Once the syndrome has resolved, steroids can be discontinued and ATO/ATRA recommenced ⁶–⁷.

References

1. Falini B, Flenghi L, Fagioli M, et al. Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibody PG-M3 (anti-PML). Blood. 1997;90(10):4046–4053.
2. van Dongen JJ, Macintyre EA, Gabert JA, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999;13(12):1901–1928.
3. Montesinos P, Bergua JM, Vellenga E, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 2009;113(4):775–83.
4. Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP. The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann. Intern. Med. 1992;117(4):292–296.
5. Jeddi R, Ghedira H, Mnif S, et al. High body mass index is an independent predictor of differentiation syndrome in patients with acute promyelocytic leukemia. Leuk. Res. 2010;34(4):545–547.
6. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113(9):1875–1891.
7. Sanz MA, Montesinos P. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood. 2014;123(18):2777–2782.