Triple Trouble.

We present a case of a 24-year-old female recently diagnosed with acute leukemia who came with complaints of fever for 14 days, progressive lower limb weakness, and multiple episodes of vomiting in the last 1 day. In nerve conduction studies, a diagnosis of Guillain-Barré syndrome (GBS) was established. Fever with thrombocytopenia workup revealed a positive dengue nonstructural protein 1 (NS1) and immunoglobulin M (IgM) report. Immunophenotyping confirmed pre-B acute lymphoblastic leukemia (ALL). As leukemia is an immunocompromised state, the peripheral nervous system vulnerability is increased, or infection could precipitate an immune neuropathy. About 10% of adult ALL presents with central nervous system (CNS) leukemias; a higher incidence is seen in mature B ALL. There is some evidence to suggest immunosuppression secondary to intensive chemotherapy (vincristine-induced dying back neuropathy), which was not started in our case. This rare combination in a short period of time with a worsening situation paralyzed the line of management. Few reports described GBS in patients with dengue in adults. The association of Guillan-Barre syndrome and ALL could be coincidental or has a pathophysiological basis and is under basic investigation.

Aggressive precursor B cell ALL of cervix with obstructive uropathy.

Involvement of the cervix with acute lymphoblastic leukaemia (ALL) is extremely rare. In this case report, we discuss an unmarried woman in her early 20s, who presented in the emergency with lower abdominal pain and irregular vaginal bleeding for 1 month. Clinical examination and imaging revealed a large cervical mass probably neoplastic with obstructive uropathy. On evaluation, she was diagnosed incidentally with CALLA-positive precursor B cell ALL in peripheral blood flow cytometry. Involvement of B cell ALL in cervical mass was confirmed by histopathological examination of cervical biopsy and immunohistochemistry markers. Her history was not suggestive of signs and symptoms pertaining to leukaemia. Literature is sparse with only a few cases reporting cervical leukaemic infiltration. The present case report is a rarest case where the primary/initial presentation of precursor B cell ALL was seen with cervical involvement and obstructive uropathy mimicking characteristics of advanced cervical malignancy.

[Blinatumomab as bridging therapy in two children with B-cell acute lymphoblastic leukemia complicated by invasive fungal disease]. / 2例急性Bæ·‹å·´ç»†èƒžç™½è¡€ç— åˆå¹¶ä¾µè¢­æ€§çœŸèŒç— å„¿ç«¥åº”ç”¨è´æž—å¦¥æ¬§å•æŠ—æ¡¥æŽ¥æ²»ç–—åˆ†æž.

This article reports two cases of children with B-cell acute lymphoblastic leukemia (B-ALL) complicated by invasive fungal disease (IFD) who received bridging treatment using blinatumomab. Case 1 was a 4-month-old female infant who experienced recurrent high fever and limb weakness during chemotherapy. Blood culture was negative, and next-generation sequencing (NGS) of peripheral blood, bronchoalveolar lavage fluid, and cerebrospinal fluid were all negative. Chest CT and cranial MRI revealed obvious infection foci. Case 2 was a 2-year-old male patient who experienced recurrent high fever with multiple inflammatory masses during chemotherapy. Candida tropicalis was detected in peripheral blood and abscess fluid using NGS, while blood culture and imaging examinations showed no obvious abnormalities. After antifungal and blinatumomab therapy, both cases showed significant improvement in symptoms, signs, and imaging, and B-ALL remained in continuous remission. The report indicates that bridging treatment with blinatumomab in children with B-ALL complicated by IFD can rebuild the immune system and control the underlying disease in the presence of immunosuppression and severe fungal infection.

Assessment of proxy-reported responses as predictors of motor and sensory peripheral neuropathy in children with B-lymphoblastic leukemia.

Chemotherapy-induced peripheral neuropathy (CIPN), a common condition in children with acute lymphoblastic leukemia, can be challenging to diagnose. Using data from Children's Oncology Group AALL0932 physical function study, we sought to determine if parent/guardian proxy-reported responses from the Pediatric Outcomes Data Collection Instrument could identify children with motor or sensory CIPN diagnosed by physical/occupational therapists (PT/OT). Four variables moderately discriminated between children with and without motor CIPN (c-index 0.76, 95% confidence interval [CI]: 0.64-0.84), but sensory and optimism-corrected models had weak discrimination (c-index sensory models 0.65, 95% CI: 0.54-0.74). New proxy-report measures are needed to identify children with PT/OT diagnosed CIPN.

Younger Matched Unrelated Donors Confer Decreased Relapse Risk Compared to Older Sibling Donors in Older Patients with B Cell Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation.

Although allogeneic hematopoietic cell transplantation (alloHCT) offers cure for older patients with acute lymphoblastic leukemia (ALL), disease relapse remains a major issue. Whether matched sibling donors (MSDs) are still the preferred donor choice compared to younger matched unrelated donors (MUDs) in the contemporary era of improved transplantation practices remains unknown. This retrospective cohort registry study queried the Center for International Blood and Marrow Transplant Research (CIBMTR) database in patients with B cell ALL (B-ALL) age ≥ 50 years undergoing alloHCT from older MSDs (age ≥ 50 years) or younger MUDs (age ≤ 35 years) between 2011 and 2018. The study included common allograft types, conditioning regimens, and graft-versus-host disease (GVHD) prophylaxis strategies. The primary outcome was relapse risk, and secondary outcomes included nonrelapse mortality (NRM), GVHD, leukemia-free survival (LFS), and overall survival (OS). Among 925 eligible patients in the study cohort, 386 underwent alloHCT with an older MSD (median donor age, 58 years) and 539 underwent alloHCT from a younger MUD (median donor age, 25 year). In multivariable analysis, younger MUDs conferred a significantly decreased risk of relapse (hazard ratio [HR], .68; P = .002) compared with older MSDs. The adjusted cumulative incidence of relapse at 5 years was significantly lower with younger MUDs than with older MSDs (26% versus 37%; P = .001). Younger MUDs were associated with a greater risk of chronic GVHD compared to older MSDs (HR, 1.33; 95% confidence interval [CI], 1.10 to 1.61; P = .003). Compared to older MSDs, younger MUDs conferred an increased NRM (HR, 1.38; P = .02) and higher adjusted cumulative incidence of NRM at 5 years (31% versus 22%; P = .006). There were no differences in post-alloHCT OS or LFS rates between younger MUDs and older MSDs (OS: HR, 1.09; [P = .37]; LFS: HR, .95 [P = .57]). The use of younger MUDs could be considered as a possible way to prevent relapse after alloHCT in older adults with ALL. Combining the use of younger MUDs with improved strategies to reduce GVHD merits further exploration to improve outcomes.

A Case of Adult Acute B-Cell Lymphoblastic Leukemia with Hypercalcemia and Osteolytic Bone Lesions.

BACKGROUND: We report a rare case of adult acute B-lymphoblastic leukemia (B-ALL) with hypercalcemia and osteolytic bone lesions in a 53-year-old man who died after chemotherapy. METHODS: The bone marrow examination was evaluated by Wright-Giemsa staining, tissue biopsy, immunohistochemical staining, and flow cytometry. Bone imaging was performed using positron emission tomography/computed tomography (PET/CT) technology. Total calcium levels were measured by biochemical analyzer. RESULTS: The result of PET/CT indicated the patient with B-ALL with severe osteolytic bone lesions. The serum total calcium level was as high as 4.09 mmol/L, and the cytokines interleukin-6 and 17A were significantly elevated. The patient was resistant to chemotherapy and had a poor prognosis. CONCLUSIONS: Hypercalcemia and osteolytic bone lesions are rare complications of adult B-ALL, and their co-occurrence may be an indicator of poor prognosis in patients with B-ALL.

HLH-like toxicities predict poor survival after the use of tisagenlecleucel in children and young adults with B-ALL.

Chimeric antigen receptor-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities (LTs) involving hyperferritinemia, multiorgan dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-cell acute lymphoblastic leukemia (B-ALL) who develop HLH-LTs, although larger outcomes analyses of children and young adults (CAYAs) with B-ALL who develop these toxicities after the administration of commercially available tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYAs with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-LTs, high-grade (HG) CRS without HLH-LTs, or no to low-grade (NLG) CRS without HLH-LTs. Primary objectives included characterizing the incidence, outcomes, and preinfusion factors associated with HLH-LTs. Among 185 CAYAs infused with tisagenlecleucel, 26 (14.1%) met the criteria for HLH-LTs. One-year overall survival and relapse-free survival were 25.7% and 4.7%, respectively, in those with HLH-LTs compared with 80.1% and 57.6%, respectively, in those without. In multivariable analysis for death, meeting criteria for HLH-LTs carried a hazard ratio of 4.61 (95% confidence interval, 2.41-8.83), controlling for disease burden, age, and sex. Patients who developed HLH-LTs had higher pretisagenlecleucel disease burden, ferritin, and C-reactive protein levels and lower platelet and absolute neutrophil counts than patients with HG- or NLG-CRS without HLH-LTs. Overall, CAYAs with B-ALL who developed HLH-LTs after tisagenlecleucel experienced high rates of relapse and nonrelapse mortality, indicating the urgent need for further investigations into prevention and optimal management of patients who develop HLH-LTs after tisagenlecleucel.

Post-Transplantation Sinusoidal Obstruction Syndrome in Adult Patients with B Cell Acute Lymphoblastic Leukemia Treated with Pretransplantation Inotuzumab.

Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication that can be observed after allogeneic hematopoietic cell transplantation (HCT). Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody-drug conjugate that has demonstrated high efficacy in relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) but is associated with an increased risk of SOS in HCT recipients. Here we aimed to examine the incidence and outcomes of SOS in 47 adult patients with R/R ALL who received inotuzumab therapy and subsequently underwent HCT at our institution. All patients received prophylactic therapy with ursodiol, and continuous low-dose heparin also was administered to patients receiving myeloablative conditioning (MAC). SOS occurred in 12 patients (26%) post-HCT, at a median onset of 11 days (range, 3 to 41 days). SOS was graded as very severe in 50% (n = 6), severe in 25% (n = 3), and mild in 25% (n = 3). All patients diagnosed with SOS received treatment with defibrotide for a median of 21 days (range, 3 to 34 days), with resolution of SOS occurring in 8 patients (67%). Mortality from SOS was 33% (n = 4) and occurred at a median of 10 days from diagnosis (range, 3 to 31 days) in patients graded as very severe (n = 3) or severe (n = 1). There were no significant differences between patients who developed SOS and those who did not develop SOS in the median time from the last dose of inotuzumab to transplantation (46 days versus 53 days; P = .37), use of an MAC regimen (42% versus 49%; P = .75), number of lines of therapy prior to inotuzumab (P = .79), median number of administered cycles of inotuzumab (2 versus 2; P = .14), or receipt of inotuzumab as the last therapy prior to HCT (67% versus 66%; P = 1.0). Sirolimus-based graft-versus-host disease (GVHD) prophylaxis was used more frequently in the SOS group (75% versus 29%; P < .01), but there was no between-group difference in the peak sirolimus level (P = .81) or the median time to peak sirolimus level (7 days versus 3.5 days; P = .39). In univariable analysis, only the use of sirolimus-based GVHD prophylaxis was significantly associated with an increased risk of SOS (hazard ratio [HR], 7.50; 95% confidence interval [CI], 1.7 to 33.6; P < .01). In the SOS group, the 100-day mortality rate was 33% (n = 4), and median overall survival (OS) post-HCT was 4.3 months (range, 0.2 to 57.2 months). In the group without SOS, the 100-day mortality rate was 14% (n = 5) and the median OS post-HCT was 10.7 months (range, .52 to 39.6 months). In this study cohort, SOS was prevalent in HCT recipients who had been treated with inotuzumab prior to transplantation, and sirolimus-based GVHD prophylaxis was a risk factor for SOS in inotuzumab recipients.

PSEUDOPANUVEITIS AS A HARBINGER FOR SYSTEMIC LEUKEMIA RECURRENCE.

PURPOSE: To describe a patient with a history of pre-B-cell acute lymphoblastic leukemia in remission, who developed recurrent alternating intraocular leukemia manifesting with pseudohypopyon, uveal mass, and serous retinal detachment. In multiple instances, this constellation of ocular findings preceded systemic leukemia recurrence. METHOD: Case report. RESULTS: A 29-year-old man with a history of pre-B-cell acute lymphoblastic leukemia, in remission after a hematopoietic stem cell transplant, presented with pseudohypopyon, uveal lesions, and serous retinal detachment of the right eye. Comprehensive workup for infectious and inflammatory etiologies was unremarkable, and a bone marrow biopsy revealed systemic recurrence of leukemia. One year later, while again in remission, the patient developed a pseudohypopyon, uveal mass, and serous retinal detachment of the other eye. Repeat bone marrow biopsy showed impending leukemia relapse, which occurred 1 month later. Orbital radiation resulted in complete ocular resolution. CONCLUSION: The constellation of pseudohypopyon, serous retinal detachment, and uveal mass (pseudopanuveitis) should be recognized as a harbinger for systemic pre-B ALL recurrence.

Blinatumomab as bridging therapy in paediatric B-cell acute lymphoblastic leukaemia complicated by invasive fungal disease.

Invasive fungal disease (IFD) remains a challenging complication of treatment for paediatric acute leukaemia. Consensus fungal treatment guidelines recommend withholding chemotherapy to facilitate immune recovery in this setting, yet prolonged delays in leukaemia therapy increase risk of relapse. Blinatumomab, a bispecific T-cell engager targeting cells expressing CD19, has shown promise for treatment of relapsed/refractory B-cell acute lymphoblastic leukaemia (B-ALL) and is associated with reduced toxicity compared to conventional chemotherapy. With close monitoring of minimal residual disease, we demonstrate that children with B-ALL can receive repeated cycles of bridging blinatumomab whilst conventional chemotherapy is withheld during treatment and recovery from IFD.

Spontaneous Hind Limb Paralysis Due to Acute Precursor B Cell Leukemia in RAG1-deficient Mice.

RAG1-deficient mice are a frequently used immunodeficient mouse strain lacking mature lymphocytes. Apart from an elevated risk for infections, no predispositions for diseases of this strain have been described so far. We here report a high incidence of spontaneous pro B cell leukemia resulting in hind limb paralysis in our colony of RAG1-deficient mice. At an age of 7-13 months, animals developed hind limb paralysis and rapid decrease of the overall health condition leading to the need of euthanasia. Histological and flow cytometric analyses as well as micro-computed tomography (micro-CT) scans revealed CD45+ CD19+ IgM- cell infiltrates in the spleen, the bone marrow, and the spinal canal. Monthly blood sampling and screening for CD19+ blast frequency in the peripheral blood was successfully established for monitoring of leukemia development before symptom onset. We conclude that facilities that breed RAG1-deficient mice should be aware of the risk of leukemia development in this strain and recommend to implement regular blood sampling for aged RAG1-deficient animals.

Management of an Immunocompromised Pediatric Patient With Multiple Hospitalizations for Symptomatic COVID-19.

Relapse of infection due to SARS-CoV-2 has been rarely described and there is little guidance regarding the management of such cases in immunocompromised hosts. We present a case of an adolescent female with B-cell acute lymphoblastic leukemia hospitalized multiple times for symptomatic SARS-CoV-2 infection who was safely treated with 2 courses of remdesivir (RDV) and has had no additional readmissions to date. Though additional studies are needed to confirm the safety and efficacy of an additional course of RDV in the setting of relapsed or prolonged severe COVID-19, our observations suggest that a second course of RDV may be considered.

Factors associated with treatment response to CD19 CAR-T therapy among a large cohort of B cell acute lymphoblastic leukemia.

CD19-targeted chimeric antigen receptor (CAR) T cell therapy has demonstrated striking responses among B cell acute lymphoblastic leukemia (B-ALL), but analyses of potential factors associated with poor response and relapse are lacking. Here, we summarize the long-term follow-up of 254 B-ALL treated with CD19 CAR-T cells from 5 clinical trials (NCT03173417, NCT02546739, and NCT03671460 retrospectively registered on May 23, 2017, March 1, 2018, and September 7, 2018, respectively, at www.clinicaltrials.gov ; ChiCTR-ONC-17012829, and ChiCTR1800016541 retrospectively registered on September 28, 2017, and June 7, 2018, at www.chictr.org.cn ). Our data showed that TP53 mutation, bone marrow blasts > 20%, prior CAR-T/blinatumomab treatment, and severe cytokine release syndrome (CRS) were associated with a lower complete remission (CR) rate while age, extramedullary disease, complex cytogenetics, history of prior transplant, prior courses of chemotherapy, CAR-T cell dose, and manufacturing source of the cellular product did not affect patients' CR rate. Risk factors related to leukemia-free survival (LFS) and overall survival (OS) were history of prior transplant, complex cytogenetics, TP53 mutation, severe CRS, neurotoxicity, and CAR-T therapy without consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT). Age and CAR-T cell dose did not influence LFS and OS. Patients with consolidative allo-HSCT after CAR-T therapy had a superior OS and LFS compared to those who did not. This benefit was also observed in both pediatric and adult patients as well as in patients either in high- or low-risk groups. This large study to identify risk factors of CR, LFS, and OS may help to maximize clinical outcomes of CAR-T therapy. Précis TP53 mutation and BM blasts > 20% are two independent factors associated with the CR rate. Patients with high tumor burden as well as those with bone marrow blasts < 5% can benefit from consolidative allo-HSCT post-CAR-T therapy.

Hematopoietic stem cell transplant in two pediatric patients testing positive for SARS-CoV-2: A case report.

BACKGROUND: The SARS-CoV-2 pandemic brought challenges to all areas of medicine. In pediatric bone marrow transplant (BMT), one of the biggest challenges was determining how and when to transplant patients infected with SARS-CoV-2 while mitigating the risks of COVID-related complications. METHODS: Our joint adult and pediatric BMT program developed protocols for performing BMT during the pandemic, including guidelines for screening and isolation. For patients who tested positive for SARS-CoV-2, the general recommendation was to delay BMT for at least 14 days from the start of infection and until symptoms improved and the patient twice tested negative by polymerase chain reaction (PCR). However, delaying BMT in patients with malignancy increases the risk of relapse. RESULTS: We opted to transplant two SARS-CoV-2 persistently PCR positive patients with leukemia at high risk of relapse. One patient passed away early post-BMT of a transplant-related complication. The other patient is currently in remission and doing well. CONCLUSION: These cases demonstrate that when the risk associated with delaying BMT is high, it may be reasonable to proceed to transplant in pediatric leukemia patients infected with SARS-CoV-2.

Scalp Nodules and Facial Droop in an Infant.

A previously healthy, term, 5-week-old girl initially presented to her primary care physician with a solitary, enlarging scalp nodule. The infant was otherwise well without additional signs or symptoms of illness. Over the next several weeks, the nodule continued to grow, and additional lesions appeared on her scalp. An ultrasound of the primary nodule revealed a hypoechoic structure favored to represent a serosanguinous fluid collection. After evaluation by general surgery and dermatology, she underwent a scalp biopsy of the largest lesion. While biopsy specimen results were pending, her parents noted that she was developing increased irritability, difficulty closing her right eye, and facial weakness. She was referred to the emergency department where a right-sided facial droop involving the brow and forehead was noted. The skin biopsy specimen results, along with subsequent laboratory studies and imaging, led to the final diagnosis.