Enhanced Survival in Acute Promyelocytic Leukemia
Enhanced Survival in Acute Promyelocytic Leukemia: A New Era of Therapeutic and Supportive Interventions
Muhammed Usman Shaikh¹, Nabiha Saeed¹
- Department of Oncology, Aga Khan University Hospital, Karachi, Pakistan
OPEN ACCESS
PUBLISHED31 January 2025
CITATION: Shaikh, M.U. and Saeed, N., 2025. Enhanced Survival in Acute Promyelocytic Leukemia: A New Era of Therapeutic and Supportive Interventions.Medical Research Archives, [online] 13(1).https://doi.org/10.18103/mra.v13i1.6119
COPYRIGHT: © 2025 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI https://doi.org/10.18103/mra.v13i1.6119
ISSN 2375-1924
ABSTRACT
Acute promyelocytic leukemia is a distinct subtype of acute myeloid leukemia characterized by a reciprocal chromosomal translocation involving the retinoic acid receptor-alpha (RARα) gene and exhibiting characteristic morphological and clinical features, with significant early mortality. With the advent of arsenic trioxide and all-trans retinoic acid the prognosis of acute promyelocytic leukemia has improved. However, early induction mortality remains a significant challenge, with hemorrhagic complications and differentiation syndrome being major contributors to morbidity and mortality.
Management of acute promyelocytic leukemia has undergone significant advancements, resulting in improved mortality rates and enhanced five-year survival rates exceeding 80%. Despite these gains, early induction mortality and differentiation syndrome remain pressing challenges.
This review underscores the importance of proactive interventions, including early administration of blood products and corticosteroids, and highlights the need for continued research into differentiation syndrome prevention strategies. Our review also underscores the need for continued research to improve outcomes in patients with APL, particularly in low- and middle-income countries where access to healthcare and treatment options are limited.
Keywords
- Acute promyelocytic leukemia
- Therapeutic interventions
- Supportive care
- Coagulopathy
- All-trans retinoic acid
Introduction
Acute promyelocytic leukemia is a relatively uncommon type of acute myeloid leukemia, accounting for 5–8% of acute myeloid leukemia cases¹. Patients are usually younger, with a median age at diagnosis of 44 years². The diagnostic parameters stand out when compared to other variants of acute myeloid leukemia, including the characteristic morphology of leukemic cells and typical flow cytometry findings, such as CD34 and HLA-DR negativity. Acute promyelocytic leukemia was previously classified as AML-M3 in the older French-American-British (FAB) classification system³, and with the advancement in cytogenetic and genetic studies, it was distinguished as acute promyelocytic leukemia with t(15;17)(q24.1;q21.1) and promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) by the World Health Organization⁴. The translocation of the PML gene on chromosome 15 to the RARA gene on chromosome 17 [i.e., t(15;17)(q24.1;q21.1)] produces a PML-RARA fusion gene that can be quantitatively monitored using polymerase chain reaction to document disease burden and ultimately confirm molecular remission⁵.
Acute promyelocytic leukemia was first described in 1957 by Hillestad and LK as a hyperacute fatal illness, with a median survival time of less than a week⁶. Although rare, even today, patients with acute promyelocytic leukemia present as an acute emergency with extremely critical conditions, such that sometimes targeted therapy cannot be administered before death. Over the last five decades, survival has improved from a median survival of less than one week to a five-year survival rate of more than 80–90%⁷. The introduction of anthracycline as a single-agent induction therapy in patients with acute promyelocytic leukemia by Bernard et al.⁸, with a remission rate of approximately 50%, has significantly improved outcomes. The introduction of all-trans retinoic acid in 1980, which is probably the first well-established example of targeted therapy, opened the floodgates for other malignancies⁹. All-trans retinoic acid revolutionized the treatment of patients with acute promyelocytic leukemia with defective homeostasis of leukemia growth¹⁴. The central nervous system and pulmonary system are the two major sites affected by hemorrhages, resulting in high morbidity and mortality¹⁵.
The management of coagulopathy has improved over time with the prophylactic administration of blood and blood products. The European LeukemiaNet and other regional guidelines provide sufficient evidence to prevent coagulopathy, including maintaining platelets at ≥30,000/µL, fibrinogen at ≥150 mg/dL, and fresh frozen plasma for deranged prothrombin time, activated partial thromboplastin time, and d-dimer for at least two weeks¹⁶.
The second important complication associated with arsenic trioxide with all-trans retinoic acid therapy is differentiation syndrome, which is now observed not only with arsenic trioxide with all-trans retinoic acid but also with novel IDH1 and IDH2 inhibitors¹⁷. The pathogenesis of differentiation syndrome is not well characterized, but the postulated mechanism likely involves capillary leak syndrome¹⁸. All-trans retinoic acid targets the retinoic acid receptor and induces differentiation of blast cells, causing cytokine release, especially in the pulmonary vasculature¹⁹. All-trans retinoic acid also alters the adhesion properties of blast cells by increasing the expression of Beta-2 integrins, further enhancing adhesion, which leads to alveolar hemorrhage in the lungs²⁰.
Common symptoms reported in differentiation syndrome include shortness of breath (84–100%), fever (74–100%), pulmonary infiltrates (52–100%), weight gain (50–100%), and effusions (36–100%)—all of which are non-specific¹⁷. Because there is no single pathogenic criterion for the diagnosis of ATRA syndrome, and because of the rarity of APL itself, there is often a delay in the proper steps to manage this complex complication.
Severe differentiation syndrome typically develops from day five onwards²¹. Laboratory abnormalities frequently seen with differentiation syndrome include leukocytosis and deranged renal function. Clinical correlation is extremely important during treatment with all-trans retinoic acid, as a transient increase in white blood cell count is not uncommon. However, a cutoff of 30 × 10⁹/L can be used to differentiate it from differentiation syndrome²². Likewise, deranged kidney function is noted in 11–66% of patients with differentiation syndrome²³.
decreasing the 5-year mortality rate from 82% to 36%¹⁰. From 2000 onwards, the incorporation of arsenic trioxide with all-trans retinoic acid in patients with low- and intermediate-risk acute promyelocytic leukemia showed superior response rates and overall survival when compared to all-trans retinoic acid plus chemotherapy¹¹. Finally, Gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody, has shown significant activity against acute promyelocytic leukemia due to the marked expression of the CD33 antigen on leukemic cells. Yasmin et al. revealed an excellent long-term outcome when Gemtuzumab was added to the induction regimen along with arsenic trioxide with all-trans retinoic acid, notably in high-risk acute promyelocytic leukemia. The introduction of oral arsenic trioxide is another milestone in the management of acute promyelocytic leukemia¹². This comprehensive review emphasizes the critical role of proactive interventions, including timely administration of blood products and corticosteroids, in improving outcomes for patients with acute promyelocytic leukemia. Furthermore, it highlights the urgent need for continued research into the prevention and management of differentiation syndrome, a potentially life-threatening complication.
Complications of treatment and therapeutic interventions:
Two notable complications commonly observed during induction therapy are coagulopathy and therapy-related differentiation syndrome, both of which are associated with high morbidity and mortality. Promyelocytes contribute to coagulopathy through two important mechanisms: one is the production of procoagulants that directly activate factor X, and the other is the expression of phospholipids that activate tissue factor, further contributing to coagulopathy¹³. Nuclear particles, present in the cell nucleus, do not have a capsule or membrane. These particles are involved in ribonucleic acid splicing and gene transcription regulation. The PML protein, which is present in these nuclear particles, fuses with the retinoic acid receptor due to the t(15;17) translocation, leading to the pathogenesis of acute promyelocytic leukemia.
The management of differentiation syndrome is not standardized, although steroids remain the mainstay of treatment²⁴. Various formulations and dosages are used for both prevention and treatment, but the duration of steroid treatment is unclear. Prospective trials comparing the efficacy of different corticosteroid formulations, including oral prednisone versus intravenous dexamethasone and methylprednisolone, are lacking²⁴. The cutoff value for WBC count, the duration of treatment, and the mode of administration are also not standardized. In the PETHEMA LPA99 trial, a 15-day duration of prophylactic prednisone was administered to all patients, regardless of white blood cells²⁵. Current recommendations for corticosteroid prophylaxis for DS are for patients with white blood cells >5 × 10⁹/L and elevated creatinine (>1.4 mg/dL)²³.
Before establishing the diagnosis of differentiation syndrome, other conditions like chest infections, volume overload, and heart failure must be excluded. Recently, the response to ruxolitinib in refractory differentiation syndrome was published; however, further evidence from large clinical trials is needed²⁶. Cytoreductive therapy is also indicated, but there is no consensus on the drug of choice. Some institutions use hydroxyurea, while others administer anthracycline or cytosine arabinoside²⁷. Gemtuzumab ozogamicin also shows a survival advantage when used in high-risk acute promyelocytic leukemia²⁸. In rare cases, if a patient develops hyperleukocytosis (typically defined as white blood cells >100 × 10⁹/L) with clinical features of leukostasis, leukapheresis is contraindicated due to the high risk of hemorrhagic death¹⁶. Unless there is rapidly rising creatinine and a need for ventilator support, treatment with arsenic trioxide with all-trans retinoic acid should be continued¹⁶,¹⁸.
The induction mortality and overall survival of patients has been improved by introducing preventive infusion of fresh frozen plasma, dexamethasone, and adequate supportive treatment during the induction chemotherapy.
Despite all the advancements in the management of acute promyelocytic leukemia, early deaths or induction mortality (usually defined as death within 30 days of starting targeted therapy) remain a concern for treating physicians. Once diagnosed, it is crucial to start all-trans retinoic acid as soon as possible, along with the prophylactic and therapeutic use of blood products.
Kantarjian et al. elaborated that the outcomes of acute myeloid leukemia are inferior in the real world when compared to results from clinical trials and academic centers²⁹,³⁰. Similarly, Lehmann found that early induction deaths are approximately 30% in acute promyelocytic leukemia, despite advancements in management over the last three decades³¹.
Below are table 1 and table 2, comparing early deaths in high- and low-income countries. It is worth noting that early death rates are nearly the same in both groups.
Table 1. Induction Deaths in Acute Promyelocytic Leukemia: Data from Canada and USA
| Research Published | Total number of patients | Deaths | Mortality % |
|---|---|---|---|
| Canada 2014 (Paulson et al³¹) | 399 | 87 | 22% |
| SEER USA 2011 (Park et al³²) | 1400 | 238 | 17% |
| Stanford USA 2012 (McClellan et al³³) | 70 | 19 | 26% |
| Georgia, USA 2014 (Annand et al³⁴) | 19 | 7 | 37% |
| Emory, USA 2014 (Iliella et al³⁴) | 75 | 19 | 25% |
In low-income countries like Pakistan, where healthcare facilities are suboptimal, there are many hurdles to achieving the outcomes described in medical literature. Even in advanced countries like the USA and Scandinavia, real-world outcomes are inferior when compared to those published in clinical trials.
Appropriate management of acute promyelocytic leukemia requires a high index of suspicion for early diagnosis due to the more common viral hemorrhagic manifestations from dengue, malaria, and other viral syndromes in our geographical region. The availability of blood products is a major issue, as most blood donations are exchange donations, and voluntary blood donation is rare. Similarly, the management of acute leukemia is very expensive, with no insurance coverage for most of the population. Setting acute promyelocytic leukemia aside, many patients with acute leukemias present late in very critical condition and die before the administration of targeted therapies.
Table 2. Induction Deaths in Acute Promyelocytic Leukemia: Data from India and Pakistan
| Research Published | Total number of patients | Deaths | Mortality % |
|---|---|---|---|
| India 2020 (Rajani et al³⁵) | 111 | 23 | 21% |
| India 2021 (Tejasvini et al³⁶) | 64 | 9 | 14% |
| India 2011 (Bajpai et al³⁷) | 33 | 8 | 24% |
| India 2024 (K Sindhusha³⁸) | 64 | 23 | 38% |
| Pakistan 2024 (Naz et al³⁹) | 50 | 7 | 14% |
| Pakistan 2008 (Shahid Raza et al⁴⁰) | 31 | 10 | 32% |
| Pakistan 2020 (Usman et al⁴¹) | 40 | 12 | 30% |
Conclusion
In conclusion, the management of acute promyelocytic leukemia is a success story, with an improvement in mortality from a few days to now more than 80% five-year survival. Early induction mortality remains a major challenge, but trends are improving with early and prophylactic administration of blood products and corticosteroids. Despite all interventions, differentiation syndrome is still one of the major complications leading to death in acute promyelocytic leukemia. We need more answers to address preventive strategies for differentiation syndrome. Awareness and education of emergency staff, as well as sensitization about the early administration of all-trans retinoic acid and blood products, is highly recommended.
Conflicts of Interest Statement:
The authors report no conflicts of interest pertaining to this work.
Funding Statement:
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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