Spontaneous remission of acute lymphoblastic leukemia: A series of nine cases and a review of literature

To report a series of acute lymphoblastic leukemia (ALL) cases with spontaneous remission and provide presenting clinical and pathologic information and details of clinical course to raise awareness among oncologists and patients.


| INTRODUCTION
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, accounting for up to 25% of cancers in children under the age of 15 years. 1,2 The prognosis of this disease depends on multiple Timothy Kirtek and Hanan Hamdan contributed equally. factors including age, clinical presentation, and genetic features.
Advances in treatment have remarkably increased overall survival and 5-year survival rate for children with ALL is now approximately 90%. 3 B-lymphoblastic leukemia (B-ALL) is the most common ALL subtype and represent 85% of pediatric cases and 75% of adult cases.
T-lymphoblastic leukemia (T-ALL) is less common, and it occurs more often in adults, accounting for 25% of cases as compared with 15% of pediatric cases. 1,2 Untreated, the natural history of ALL is that of an uncontrolled proliferation of neoplastic lymphoblasts, resulting in decreased production of normal functional cells. The resulting sequelae include progressively worsening anemia, bleeding, infection, and organ failure that is universally fatal.
Spontaneous remission of ALL is a phenomenon that has been gaining increased attention in recent years. Spontaneous remission is defined by a partial or complete disappearance of a malignant disease without initiating any specific chemotherapy or by using a treatment regarded as insufficient for a response. 3,4 Spontaneous remission without chemotherapy in ALL was first described in 1878 by Eisenlohr in a patient following a typhoid infection. 5 Spontaneous remission is rare, and commonly follows a presentation of fever or sepsis followed by rapid but temporary remission. 2 The mechanism by which spontaneous remission in ALL occurs is poorly understood. Many of the reported cases have been associated with acute stress-inducing conditions, particularly infections, and tumor lysis syndrome. Literature review of clinical research shows that the exact mechanisms through which inflammation and its treatment modalities are not fully explained. 6 In addition, inflammation in the setting of malignancy does not lead to long-term leukemia remission, and spontaneous remission cases are typically followed by relapse. 7 The goal of our study is to report on a series of ALL patients who experienced spontaneous remission and provide presenting clinical and pathologic information and details of clinical course of these patients with goals of raising awareness of this entity.

| PATIENTS AND METHODS
We retrospectively analyzed nine cases of ALL with spontaneous remission. Diagnosis was confirmed in all patients by morphology and flow cytometry on routine clinical and pathologic evaluation. Diagnostic and any follow-up pathology results-including morphology, flow cytometry and any ancillary testing-were recorded. Clinical information was derived from retrospective medical record review. This study was approved by an IRB in all participating institutions. Complete remission (CR) is clinically defined as peripheral blood neutrophil count ≥1000/μL and platelet count ≥100 000/μL, with no circulating blasts and blasts in bone marrow <5%. 1 Upon diagnosis, antibiotic, antifungal, and antiviral (oseltamivir) prophylaxis were given according to institutional standards.
We performed a pubmed search to identify reported patients with spontaneous remission of their ALL.

| RESULTS
We identified nine patients who demonstrated a spontaneous remission after a diagnosis of ALL. The detailed clinicopathologic findings are shown in Tables 1 and 2. Patients ranged in age from 2 to 12 years of age (mean 5.4 years). All except one patient presented with cytopenias (Table 1). All presented with signs and symptoms of some inciting infectious (bacterial and viral) process, including upper respiratory or GI symptoms, mucosal inflammation, or abscess formation. Overall, some of the most common presenting symptoms included fever, fatigue, cough, and emesis. One patient presented with macroorchidism, that was clinically attributed to inflammation.

| Clinical course
None of the nine patients received systemic chemotherapy, and only one patient received intrathecal cytarabine. Seven patients received the following: steroids (n = 5), antibiotics (n = 2), and supportive blood product transfusions (n = 4). Two patients received no reported treatments at all. All nine patients achieved spontaneous remission as confirmed by flow cytometry and/or bone marrow biopsy without chemotherapeutic intervention, although steroid therapy could be considered as partial therapeutics. Time to remission from presentation ranged from 1 to 8 weeks (mean 2.8 weeks). Clinical recovery was also documented with recovery of blood counts and resolution of infections. Eight patients suffered a reemergence of ALL by flow cytometry and/or bone marrow biopsy ranging from 2 to 24 weeks after documented remission (mean 8.4 weeks). One patient was lost to follow up after remission. Four patients achieved sustained remission following standard chemotherapy while the other 5 were lost to follow-up. Time to spontaneous remission varied between 1 and 6 weeks, with remission studies showing recovery of complete blood count with differential except for one case, who had persistent cytopenias. Time from spontaneous remission to reemergence ranged from 2 weeks to 7 months.

| Comprehensive review of literature
Our results are concordant with previously reported cases of spontaneous remission of ALL reported in the literature. [8][9][10][11][12][13][14][15] Analysis of nine case reports identified from literature search (Table 3) showed reported age range from 15 months to 50 years (three pediatric cases, and seven adult cases). All reported patients presented with either viral or bacterial infection. Similar presenting symptoms were reported including fever, cough, and fatigue as we found in our series. The reported cases either had bi-or-pancytopenia at presentation, and shared similar blasts phenotype on flow cytometry with variable percentages (3%-93%). All patients received antibiotics, antivirals, steroids, blood product transfusions, and/or supportive treatment without any chemotherapy. Time to remission of ALL from presentation ranged from 5 days to 7 weeks (mean 4 weeks) with normalization of blood counts and absence of abnormal blasts in bone marrow. All cases experienced a relapse with time ranging from 2 weeks to 14 months with relapsed blast phenotype similar to reported phenotype at presentation. [8][9][10][11][12][13][14][15] All but two patients reached CR after chemotherapy induction, while one was lost to follow-up and the other patient died from unrelated causes. 16 T A B L E 1 Summary of clinical presentation of the nine patients with spontaneous remission.

| DISCUSSION
Leading theories of spontaneous ALL remission suggest that stimulation by corticosteroids and/or cytokine release may have antileukemic effects. The cases we report here are similar to other reported cases of spontaneous remission of ALL that occurred in the setting of acute infection and resolved following resolution of the infection and/or steroid treatment. 4 Corticosteroids are well established as a highly effective component of treatment to induce remission in ALL; thus, processes that increase endogenous corticosteroid production may be responsible for cases of spontaneous ALL remission. 17 The stress response induced by infectious processes can lead to increased corticosteroid production in response to the stressors. 18 In addition, blood product transfusions have been associated with increased corticosteroid production. 13 These processes can lead to steady, elevated levels of circulating corticosteroids which may rise to antileukemic levels and induce remission. All nine patients in our series had exposure to one or all of these scenarios.
This data supports the theory that elevated endogenous steroid production may be a mechanism of spontaneous remission in ALL. 19 However, exogenous steroid administration by a pediatrician in clinical practice is relatively common in the presentation of nascent B-ALL cases, and the lack of documentation may not be proof of absence.
All case reports of spontaneous remissions of ALL in the literature [8][9][10][11][12][13][14][15] demonstrate a timeline of relatively fast, short-term remission preceded by fever or sepsis (within 5 days-5 weeks). Because of the antileukemic effects of corticosteroids, remission after their use may not be considered as spontaneous. However, treatment with antibiotics and blood transfusions can also contribute to spontaneous remission, 13 and spontaneous remission unrelated to transfusion, infection or corticosteroids have been documented previously. 20,21 As in our cases, bacteremia was more common among CR cases compared with partial remission. 8 Moreover, infections often lead to production of granulocyte colony-stimulating factor which could potentiate the effects of cytotoxic cells against the leukemic cells. 22 The underlying mechanisms here include increased levels of interleukin-2 (IL-2) leading to the activation of natural killer cells (NK), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-1, IL-6, and heat shock proteins, and leukocytoclastic vasculitis. 19 26 Some studies have postulated that these pro-inflammatory cytokines can switch the equilibrium from a pro-leukemic to an antileukemia medium and cause a transient remission of ALL and a suppression of hematopoiesis resulting in aplasia. 26 Spontaneous remission of tumor can be induced by shifting the immune system into an activated tumor microenvironment (TME) through fungal infections. 6,18 The underlying process may include inhibition of the phoenix rising pathway responsible for leukemia regrowth. 27 Fungal TLR ligands could provoke normal and malignant hematopoiesis. 28 Therefore, their activation may act synergistically on the antileukemic effects of the TME. 17 Corthals et al. 25

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.