Impact of triple intrathecal prophylaxis in acute lymphoblastic leukemia adults receiving HyperCVAD: A COVID-19 practice change.

Treatment of acute lymphoblastic leukemia (ALL) requires both systemically and locally directed therapies to prevent central nervous system (CNS) recurrence. In response to restrictions brought on by the COVID-19 pandemic, our institution adopted triple intrathecal (IT) chemotherapy for CNS prophylaxis during HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine). We retrospectively reviewed records of newly diagnosed adult all patients who were consecutively treated with HyperCVAD between January 2011 and July 2022. Outcomes of patients who received triple IT chemotherapy and standard of care (SOC) CNS prophylaxis were compared. The primary endpoint was CNS relapse-free survival (RFS) while secondary endpoints included cumulative incidence of relapse, overall survival, number of outpatient, and total ITs per patient, and CNS treatment-related toxicities. A total of 37 patients including 21 in the triple IT and 16 in the SOC cohorts were evaluated. There were no differences between the triple IT and SOC cohorts with respect to CNS-RFS (89.6% vs. 80.4%; HR, 1.55; 95% CI, 0.45-5.39; p = .49), cumulative incidence of relapse (8.9% vs. 19.6%; HR, 1.14; 95% CI, 0.3-5.3; p = .87), and overall survival (89.6% vs. 85.7%; HR, 0.91; 95% CI, 0.20-4.21; p = .90) at 2-years. Significantly fewer IT doses were administered in the triple IT cohort (p = .011) and the number of additional outpatient appointments to administer IT chemotherapy were markedly reduced as 98.6% of IT doses were administered during scheduled admissions compared to 76.8% (p < .001). The adoption of triple IT chemotherapy did not increase CNS treatment-related toxicities but rather, the inverse was observed. Triple IT chemotherapy during HyperCVAD represents a feasible alternative to SOC CNS prophylaxis, especially during times of resource restriction and when minimization of patient exposures is desired.

Ponatinib-Associated Cutaneous Eruptions-A Case Series and Review of Clinicopathologic Findings.

ABSTRACT: Ponatinib is a third-generation tyrosine kinase inhibitor used to treat chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia. Cutaneous toxicities are a commonly reported side effect of ponatinib treatment with "rash" being one of the most common. Specific subtypes are infrequently reported, but include hyperkeratotic, folliculocentric, ichthyosiform, and pityriasis rubra pilaris-like eruptions. Herein, we highlight the clinicopathologic features of 2 cases of ponatinib-induced pityriasis rubra pilaris-like eruptions. We also classify the clinical and histopathologic features of all previously reported ponatinib-associated eruptions in the literature and discuss treatment and potential diagnostic pitfalls.

Severe acute respiratory syndrome coronavirus-2 Alpha variant (B.1.1.7), original wild-type severe acute respiratory syndrome coronavirus 2, and cytomegalovirus co-infection in a young adult with acute lymphoblastic leukemia, case report, and review of the possible cytomegalovirus reactivation mechanisms.

BACKGROUND: Like other viral infections, severe acute respiratory syndrome coronavirus-2 infection could affect different human body systems, including host immune responses. Three years after its pandemic, we learn more about this novel coronavirus. As we expected, different co-infections with various organisms, such as viruses, bacteria, and even fungi, have been reported. However, concurrent infection with two severe acute respiratory syndrome coronavirus-2 strains and cytomegalovirus is extremely unusual. We have only a rudimentary understanding of such co-infections and their long-term consequences for patients with cancer. CASE PRESENTATION: An 18-year-old young Iranian adult with acute lymphoblastic leukemia presented with abdominal pain, diarrhea, nausea, and vomiting following a recent history of severe acute respiratory syndrome coronavirus-2 infection. The patient never experienced respiratory symptoms, and the chest imaging study was normal on admission. His primary laboratory investigation revealed prerenal azotemia and severe abnormal liver function tests (blood urea nitrogen 32 mg/dL, creatinine 1.75 mg/dL, prothrombin time 66 s, partial thromboplastin time 44.5 s, international normalized ratio 5.14, total bilirubin 2.9 mg/dL, and direct bilirubin 2.59 mg/dL). Cytomegalovirus disease was diagnosed by polymerase chain reaction in his blood and stool samples. The patient's gastrointestinal signs and symptoms improved shortly after receiving intravenous ganciclovir treatment. His gastrointestinal symptoms continued intermittently for weeks despite maintenance valganciclovir prescription, necessitating frequent hospitalizations. The patient was complicated by the recurrence of gastrointestinal symptoms during the sixth hospitalization, even though he had no respiratory symptoms, and the nasopharyngeal test revealed severe acute respiratory syndrome coronavirus-2 Wuhan strain for the first time. Remdesivir and valganciclovir were administrated due to persistent enteritis and evidence of intestinal tissue invasion by severe acute respiratory syndrome coronavirus 2 and cytomegalovirus on multiple intestinal biopsies, which led to partial clinical responses. Cytomegalovirus and severe acute respiratory syndrome coronavirus-2 fecal shedding continued for more than 6 months despite repeated antiviral therapy, and the Wuhan and Alpha strains were also detected in his nasopharyngeal samples through repeated sampling (confirmed by four nasopharyngeal sampling and multiple stool specimens and several intestinal biopsies). Finally, during the Delta-variant (B.1.617.2) outbreak in Iran, the patient was admitted again with febrile neutropenia and decreased level of consciousness, necessitating respiratory support and mechanical ventilation. During the Delta-variant peak, the patient's nasopharyngeal sample once more tested positive for severe acute respiratory syndrome coronavirus 2. The patient died a few days later from cardiopulmonary arrest. CONCLUSION: The coronavirus disease 2019 pandemic has encountered patients with cancer with critical diagnostic and treatment challenges. Patients who are immunocompromised may co-infect with multiple severe acute respiratory syndrome coronavirus-2 strains and cytomegalovirus, and even with timely diagnosis and treatment, the prognosis may be poor.

FIP1L1-PDGFRA fusion gene in T-lymphoblastic lymphoma: A case report.

BACKGROUND: T-lymphoblastic lymphoma (T-LBL) is an aggressive malignancy of T-lymphoid precursors, rarely co-occurring with myeloid/lymphoid neoplasms with eosinophilia (M/LNs-Eo), with consequent rearrangement of tyrosine kinase (TK)-related genes. The FIP1L1-PDGFRA fusion gene is the most frequent molecular abnormality seen in eosinophilia-associated myeloproliferative disorders, but is also present in acute myeloid leukemia (AML), T-lymphoblastic leukemia/lymphoma (TLL), or both simultaneously. T-LBL mainly affects children and young adults, involving lymph node, bone marrow, and thymus. It represents about 85% of all immature lymphoblastic lymphomas, whereas immature B-cell lymphomas comprise approximately 15% of all cases of LBL. CASE: In this case report, we present an example of T cell lymphoblastic lymphoma with coexistent eosinophelia, treated successfully with a tyrosine-kinase inhibitor (TKI). CONCLUSION: FIP1L1-PDGFRA-positive T-LBL and myeloproliferative disorders have excellent response to low-dose treatment with (TKI) imatinib. Most patients achieve rapid and complete hematologic and molecular remission within weeks.

Novel coronavirus infection (COVID-19) in a 12-year-old boy with acute lymphoblastic leukemia.

Pediatric acute lymphoblastic leukemia (ALL) with COVID-19 might still have a risk of severe infection due to immunocompromised condition. The clinical features in oncology population are quite similar to those of previous reports in general pediatric cases. Chemotherapy should be arranged individually to balance the risk between leukemia progressivity itself and COVID-19 complications. Interruptions of therapy must be thought in cases with severe or symptomatic infection of severe acute respiratory syndrome-CoV-2. In this case report, chemotherapy will be started 1 week after the improvement of general condition. Chemotherapy should not be postponed for >14 days.

Cerebrovascular accident in a child with precursor B-cell acute lymphoblastic leukemia and coronavirus disease 2019: a case report.

BACKGROUND: Coronavirus disease 2019 can lead to rare but severe and life-threatening diseases in susceptible high-risk populations, including patients with immunodeficiency. A rare event in this report is stroke following COVID-19 disease in a patient with an immunocompromised background due to leukemia and anti-cancer treatments. CASE PRESENTATION: A 6-year-old iranian girl with precursor B-cell leukemia receiving vincristine therapy presented with fever and absolute neutrophil count < 500. Her severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test was positive. During hospitalization, she had abrupt onset tachypnea, reduced O2 saturation, and generalized tonic-clonic seizures treated with phenytoin and levetiracetam. Right parietal lobe ischemia was found on a brain computed tomography scan, and the cerebrospinal fluid polymerase chain reaction test was positive for severe acute respiratory syndrome coronavirus 2. Several days later, she developed lower extremity paralysis and speech impairment, so speech therapy and physiotherapy were initiated. The patient also received dexamethasone, mannitol, heparin, and remdesivir. She was discharged with enoxaparin and levetiracetam. Chemotherapy resumed 2 weeks following discharge. Her speech and walking improved after 10 months of follow-up, and bone marrow aspiration showed total remission. CONCLUSION: Owing to the link between coronavirus disease 2019 and hematologic cancers with hypercoagulopathy and the tendency of patients with leukemia to have coronavirus disease 2019 complications, children with leukemia as well as suspected coronavirus disease 2019 must be hospitalized to prevent blood clot formation.

JAK: Not Just Another Kinase.

The JAK/STAT axis is implicated in cancer, inflammation, and immunity. Numerous cytokines/growth factors affect JAK/STAT signaling. JAKs (JAK1, JAK2, JAK3, and TYK2) noncovalently associate with cytokine receptors, mediate receptor tyrosine phosphorylation, and recruit ≥1 STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6). Tyrosine-phosphorylated STATs dimerize and are then transported into the nucleus to function as transcription factors. Signaling is attenuated by specific suppressor of cytokine signaling proteins, creating a negative feedback loop. Both germline mutations and polymorphisms of JAK family members correlate with specific diseases: Systemic lupus erythematosus (TYK2 polymorphisms); severe combined immunodeficiency (JAK3 mutations); pediatric acute lymphoblastic leukemia (TYK2 mutations); and hereditary thrombocytosis (JAK2 mutations). Somatic gain-of-function JAK mutations mainly occur in hematologic malignancies, with the activating JAK2 V617F being a myeloproliferative disorder hallmark; it is also seen in clonal hematopoiesis of indeterminate potential. Several T-cell malignancies, as well as B-cell acute lymphoblastic leukemia, and acute megakaryoblastic leukemia also harbor JAK family somatic alterations. On the other hand, JAK2 copy-number loss is associated with immune checkpoint inhibitor resistance. JAK inhibitors (jakinibs) have been deployed in many conditions with JAK activation; they are approved in myeloproliferative disorders, rheumatoid and psoriatic arthritis, atopic dermatitis, ulcerative colitis, graft-versus-host disease, alopecia areata, ankylosing spondylitis, and in patients hospitalized for COVID-19. Clinical trials are investigating jakinibs in multiple other autoimmune/inflammatory conditions. Furthermore, dermatologic and neurologic improvements have been observed in children with Aicardi-Goutieres syndrome (a genetic interferonopathy) treated with JAK inhibitors.

The diagnostic dilemma of idiopathic intracranial hypertension in a child with acute lymphoblastic leukemia: COVID-19 or cytosine arabinoside?

BACKGROUND: Idiopathic intracranial hypertension is a rare neurological condition among children. Its manifestations vary from mild headaches to loss of vision. Although rare, COVID-19 infection and high dose cytosine arabinoside have been reported as risk factors for this neurological disorder. In patients with acute leukemia, idiopathic intracranial hypertension diagnosis is simple, but finding its etiology can be difficult. CASE PRESENTATION: We report a case of a 9-year-old boy with an ongoing treatment for T-acute lymphoblastic leukemia presenting with persistent headaches and diplopia. A diagnosis of idiopathic intracranial hypertension was retained based on clinical, imaging and laboratory findings. Due to its rarity, we describe its clinical and therapeutic features and highlight the challenging etiological dilemma between COVID-19 infection and high dose cytosine arabinoside administration. CONCLUSION: Persistent headache in a pediatric patient with leukemia can be due to many neurological disorders other than leukemic relapse. Given the improvement of the neurological symptoms after the SARS-CoV-2 PCR negativization and the successful re-introduction of high dose cytosine Arabinoside, the diagnosis of idiopathic intracranial hypertension associated with Covid-19 infection was withheld.

How essential are in-person clinic visits during maintenance treatment of children with acute lymphoblastic leukemia?

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Treatment consists of an initial intensive phase of chemotherapy, followed by a prolonged period of maintenance chemotherapy intended to reduce the risk of relapse. During the COVID-19 pandemic, the need arose to identify and reduce non-essential hospital visits. OBJECTIVE: We aimed to determine which proportion of in-person clinic visits during ALL maintenance therapy was associated with a change of management based on the results of the physical examination. PATIENTS AND METHODS: Medical records of children receiving maintenance chemotherapy for B-precursor ALL between September 2019 and February 2020 were reviewed. Visits with a new finding on physical examination were divided into those where an in-person assessment was deemed essential versus not essential. Finally, we determined the proportion of essential in-person visits that resulted in a change of management. RESULTS: A total of 240 maintenance visits by 75 children were analyzed. An abnormal finding on physical examination was noted during 20 visits (8.3%). Of those, 14 (5.8%) uncovered a new finding, six (2.5%) were classified as "in-person visit essential," and among those six visits, three (1.2%) resulted in a change of patient management (one for acute otitis media, one for wheezing, and one for limp). CONCLUSION: Our findings support the evaluation of care delivery models other than in-person visits during ALL maintenance therapy. A prospective study is required to delineate criteria, benefits/risks, and families' perspectives associated with virtual care delivery and the optimal frequency of in-person visits.

Isolated CNS Relapse in 2 High-Risk B-cell Acute Lymphoblastic Leukemia Patients Following SARS-CoV-2 Infection.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy with a highly favorable overall prognosis. Central nervous system (CNS) relapse of B-ALL is relatively rare and is associated with inferior survival outcomes. We present two patients with B-ALL who developed isolated CNS relapse following confirmed infection with severe acute respiratory syndrome coronavirus 2. In addition to individual and disease factors, we posit that delays in therapy together with immune system modulation because of severe acute respiratory syndrome coronavirus 2 may account for these 2 cases of CNS relapsed B-ALL. We report on this clinical observation to raise awareness of this potential association.

Immune thrombocytopenic purpura secondary to SARS-CoV-2 infection in a child with acute lymphoblastic leukaemia: a case report and review of literature.

Immune thrombocytopenic purpura (ITP) is characterised by isolated thrombocytopenia which may be idiopathic or due to a secondary aetiology. ITP is being increasingly recognised secondary to SARS-CoV-2 infection in the current pandemic. Here, we report a case of a five-and-a-half-year-old female child on maintenance chemotherapy for acute lymphoblastic leukaemia who subsequently developed ITP secondary to SARS-CoV-2 infection. Our patient had prolonged thrombocytopenia secondary to ITP, requiring the use of second-line agents including romiplostim and eltrombopag. This is a unique case where ITP was recognised secondary to SARS-CoV-2. In such cases of thrombocytopenia, ITP should be considered as an important differential in addition to relapse of leukaemia or thrombocytopenia due to chemotherapy drugs.

Safety of administration of BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine in youths and young adults with a history of acute lymphoblastic leukemia and allergy to PEG-asparaginase.

Vaccinationis a critical tool in the prevention of COVID-19 infection for individuals and for communities. The mRNA vaccines contain polyethylene glycol (PEG) as a stabilizer. Currently, in North America, only the BNT162b2 (Pfizer-BioNTech) mRNA vaccine is approved for individuals aged 12-17. Most patients treated with contemporary regimens for acute lymphoblastic leukemia receive PEG-asparaginase (PEG-ASNase) and 10%-30% will develop allergic reactions. Optimizing access and safety for vaccine administration for these patients is critical. This report describes a process developed to support COVID vaccination in a cohort of adolescents and young adults with a history of PEG-ASNase allergy.

Successful treatment of COVID-19 infection with convalescent plasma in B-cell-depleted patients may promote cellular immunity.

Treatment with convalescent plasma has been shown to be safe in coronavirus disease in 2019 (COVID-19) infection, although efficacy reported in immunocompetent patients varies. Nevertheless, neutralizing antibodies are a key requisite in the fight against viral infections. Patients depleted of antibody-producing B cells, such as those treated with rituximab (anti-CD20) for hematological malignancies, lack a fundamental part of their adaptive immunity. Treatment with convalescent plasma appears to be of general benefit in this particularly vulnerable cohort. We analyzed clinical course and inflammation markers of three B-cell-depleted patients suffering from COVID-19 who were treated with convalescent plasma. In addition, we measured serum antibody levels as well as peripheral blood CD38/HLA-DR-positive T-cells ex vivo and CD137-positive T-cells after in vitro stimulation with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides in these patients. We observed that therapy with convalescent plasma was effective in all three patients and analysis of CD137-positive T-cells after stimulation with SARS-CoV-2 peptides showed an increase in peptide-specific T-cells after application of convalescent plasma. In conclusion, we here demonstrate efficacy of convalescent plasma therapy in three B-cell-depleted patients and present data that suggest that while application of convalescent plasma elevates systemic antibody levels only transiently, it may also boost specific T-cell responses.

Isolated optic nerve involvement in acute lymphoblastic leukaemia: a red flag for early relapse.

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer, with 70%-80% of cases curable with modern chemotherapy. However, 20% of the cases suffer from disease relapse with bone marrow being the most common site. Isolated ocular involvement as the first sign of relapse is extremely rare, occurring in less than 2.2% of cases. The presentation of optic nerve involvement in leukaemia represents a visual emergency and a sign of isolated central nervous system relapse even in the absence of abnormal cerebrospinal fluid cytology. This case highlights the importance of routine ophthalmic screening in ALL even during maintenance phase and prompt initiation of treatment in cases with isolated optic nerve involvement.

COVID-19-related Gastrointestinal Bleeding in a Pediatric Patient With ALL.

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus-2. Patients with hematologic malignancies have been shown to have higher risk of mortality due to COVID-19 than reported in the general adult population. Reports on acute lymphoblastic leukemia and COVID in children are scarce. We present a case of an 11-year-old male patient undergoing treatment for B-cell acute lymphoblastic leukemia with an atypical course of COVID-19. The patient received a positive result of the syndrome coronavirus-2 polymerase chain reaction test performed due to epidemiologic reasons. The chemotherapy was continued since the patient had no clinical signs of COVID-19. The disease started with intensive gastrointestinal bleeding, followed by severe respiratory tract infection over 2 weeks later.