Use of convalescent plasma in COVID-19 patients with immunosuppression.

In the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID-19), including among patients with innate or acquired immunosuppression. However, the association between COVID-19-associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched-control registry study of 143 COVID-19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID-19 patients with immunosuppression. We review clinical features and treatment protocols of COVID-19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID-19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune-deficient and immune-suppressed patients with COVID-19 warrants further investigation.

Allopurinol to Prevent Mercaptopurine Adverse Effects in Children and Young Adults With Acute Lymphoblastic Leukemia.

Mercaptopurine (6MP) is used to treat acute lymphoblastic leukemia (ALL) and is metabolized by hypoxanthine guanine phosphoribosal transferase to form 6-thioguanine nucleotide (6TGN). It is also metabolized by thiopurine methyl-transferase to produce 6-methylmercaptopurine (6MMP). Elevated levels of 6MMP have been associated with toxic effects that may interfere with therapy. Allopurinol is known to inhibit thiopurine methyl-transferase which reduces red cell 6MMP and increases 6TGN. Allopurinol has been utilized successfully in adult and pediatric patients with inflammatory bowel disease who have experienced 6MMP related gastrointestinal toxicity. Between August 2015 and August 2018 we started 25 patients with ALL in maintenance on allopurinol in combination with a reduced dose of 6MP. They all had unacceptable side-effects from elevated 6MMP, including abdominal pain, nausea, vomiting, decreased appetite, hypoglycemia, fatigue, and liver toxicity. In addition many had a facial rash. All patients showed resolution of symptoms within a few weeks after starting allopurinol. The red cell levels of 6MMP rapidly declined in the first month. The red cell levels of 6TGN transiently increased in spite of the lower 6MP dose. There was no decrease in absolute neutrophil count or hemoglobin. Platelets decreased slightly not requiring therapy modification. Elevated bilirubin normalized, and alanine aminotransferase decreased significantly with most normalizing. All patients continued on allopurinol with reduced dose 6MP until completing therapy. Allopurinol, in conjunction with a reduced dose of 6MP, effectively resolves 6MMP related side-effects in ALL patients on maintenance chemotherapy. This approach may lead to increased adherence to oral 6MP during ALL maintenance in patients with 6MMP induced side-effects.

Langerhans cell histiocytosis with BRAF p.N486_P490del or MAP2K1 p.K57_G61del treated by the MEK inhibitor trametinib.

Activating variants of the MAPK pathway have been found in some Langerhans cell histiocytosis (LCH) lesions. Inhibition of the MAPK pathway with trametinib (MEK inhibitor) has been shown to induce responses in LCH patients. Two adolescent males with LCH driven by BRAF p.N486_P490del have received trametinib for >1 year with no reactivation in one and partial response in another (including stable lung disease). A third male with neonatal LCH and MAP2K1p.K57_G61del had a complete response to trametinib with no active disease after 22 months. All patients continue on trametinib monotherapy with tolerable skin and creatine phosphokinase toxicity.

Comparison of self-report and electronic monitoring of 6MP intake in childhood ALL: a Children's Oncology Group study.

Adequate exposure to oral 6-mercaptopurine (6MP) during maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is critical for sustaining durable remissions; accuracy of self-reported 6MP intake is unknown. We aimed to directly compare self-report to electronic monitoring (Medication Event Monitoring System [MEMS]) and identify predictors of overreporting in a cohort of 416 children with ALL in first remission over 4 study months (1344 patient-months for the cohort) during maintenance therapy. Patients were classified as "perfect reporters" (self-report agreed with MEMS), "overreporters" (self-report was higher than MEMS by ≥5 days/month for ≥50% of study months), and "others" (not meeting criteria for perfect reporter or overreporter). Multivariable logistic regression examined sociodemographic and clinical characteristics, 6MP dose intensity, TPMT genotype, thioguanine nucleotide levels, and 6MP nonadherence (MEMS-based adherence <95%) associated with the overreporter phenotype; generalized estimating equations compared 6MP intake by self-report and MEMS. Self-reported 6MP intake exceeded MEMS at least some of the time in 84% of patients. Fifty patients (12%) were classified as perfect reporters, 98 (23.6%) as overreporters, 2 (0.5%) as underreporters, and 266 (63.9%) as others. In multivariable analysis, the following variables were associated with the overreporter phenotype: non-white race: Hispanic, odds ratio (OR), 2.4, P = .02; Asian, OR, 3.1, P = .02; African American, P < .001; paternal education less than college (OR, 1.4, P = .05); and 6MP nonadherence (OR, 9.4, P < .001). Self-report of 6MP intake in childhood ALL overestimates true intake, particularly in nonadherent patients, and should be used with caution.

Methotrexate Polyglutamate Values in Children and Adolescents With Acute Lymphoblastic Leukemia During Maintenance Therapy.

Inadequate adherence to maintenance therapy is a major cause of relapse in patients with acute lymphoblastic leukemia (ALL). Therapeutic monitoring of mercaptopurine (thiopurine) red cell metabolites to assess adherence has been available for many years. Recently a clinical laboratory improvement amendments of 1988-approved test for methotrexate with three polyglutamate residues (MTXPG3) measured in peripheral blood red cells was approved. MTXPG3 is the primary intracellular metabolite of methotrexate, and like thiopurine metabolites, is retained for the life of the red cell giving an estimate of drug exposure over time. Normative values for MTXPG3 are available for adults and children with rheumatoid arthritis on methotrexate monotherapy, which are not applicable for patients with ALL on maintenance. Older literature on the MTXPG3 fraction in children with ALL is limited. We examined the MTXPG3 levels from 123 samples in 76 patients with ALL on maintenance oral methotrexate and mercaptopurine that were collected for clinical care. Male individuals had significantly higher MTXPG3 levels than female individuals which was unrelated to absolute neutrophil count, age, serum creatinine, and average doses of methotrexate or mercaptopurine. The MTXPG3 5th, 10th, 90th, and 95th percentile values are 0, 8.4, 53, and 64, respectively with a median of 24.7 nmol/L. The low 5th percentile MTXPG3 reflects 6 samples from 3 patients, age 16 to 21 years that were considered poorly adherent before collecting the specimen. As with red cell thiopurine (mercaptopurine) metabolites, MTXPG3 normative values may provide useful information to monitor for poor patient adherence or methotrexate toxicity during maintenance chemotherapy in ALL.

Switching to Bortezomib may Improve Recovery From Severe Vincristine Neuropathy in Pediatric Acute Lymphoblastic Leukemia.

PURPOSE: The purpose of this study was to evaluate the impact of switching patients being treated for acute lymphoblastic leukemia (ALL) from vincristine to bortezomib. PATIENTS AND METHODS: A total of 20 patients with ALL were switched from vincristine to bortezomib (1.3 mg/m/dose) because of worsening neuropathy despite physical therapy interventions (n=18) or at increased risk of neuropathy (n=2). Relapse rates were compared with 56 vincristine-only patients matched by prognostic factors. Maintenance blood counts in bortezomib patients were compared with cooperative group data using vincristine during maintenance. In addition, 6 evaluable patients were assessed for neuropathy using the pediatric-modified total neuropathy score. Neuropathy scores were collected during treatment with vincristine and after switching to bortezomib. RESULTS: After a median follow-up of 3.5 years the relapse rate in patients switched to bortezomib was nonsignificantly different than those remaining on vincristine. Patients on monthly bortezomib had statistically significantly lower platelet counts that did not require transfusions or dose adjustment. Total neuropathy for all 6 cases decreased significantly when switched to bortezomib from vincristine (P=0.015), with motor neuropathy declines in 5 of 6 subjects. CONCLUSIONS: Bortezomib substitution for vincristine in ALL treatment is a potential strategy to mitigate severe vincristine neuropathy. These findings should be confirmed in a randomized clinical trial to further assess benefits and risks of this approach.

Symptomatic Hyperammonemia With Erwinia chrysanthemi-derived Asparaginase in Pediatric Leukemia Patients.

Erwinia chrysanthemi-derived asparaginase is increasingly integral to acute lymphoblastic leukemia therapy. In our series, 16% of patients developed symptomatic hyperammonemia following Erwinia administration with symptoms including refractory nausea, vomiting, profound fatigue, malaise, and coma. This series of patients receiving Erwinia indicates higher than expected incidence of hyperammonemia, correlation between ammonia and asparaginase levels and therapeutic asparaginase activity levels despite dose reduction. The series provides evidence for investigation into which patients require intervention to prevent toxicity, which patients may have ammonia levels used as an asparaginase activity surrogate and which patients may achieve equivalent efficacy with abridged dosing.

6MP adherence in a multiracial cohort of children with acute lymphoblastic leukemia: a Children's Oncology Group study.

Durable remissions in children with acute lymphoblastic leukemia (ALL) require a 2-year maintenance phase that includes daily oral 6-mercaptopurine (6MP). Adherence to oral 6MP among Asian-American and African-American children with ALL is unknown. We enrolled 298 children with ALL (71 Asian Americans, 68 African Americans, and 159 non-Hispanic whites) receiving oral 6MP for the maintenance phase. Adherence was measured electronically for 39 803 person-days. Adherence declined from 95.0% (month 1) to 91.8% (month 5, P < .0001). Adherence rates were significantly (P < .0001) lower in Asian Americans (90.0% ± 4.9%) and African Americans (87.1% ± 4.4%), as compared with non-Hispanic whites (95.2% ± 1.3%). Race-specific sociodemographic characteristics helped explain poor adherence (African Americans: low maternal education [less than a college degree: 78.9%, vs at least college degree: 94.6%; P < .0001]; Asian Americans: low-income households [<$50 000: 84.5%, vs ≥$50 000: 96.7%; P = .04]; households without mothers as full-time caregivers [85.6%] vs households with mothers as full-time caregivers [97.2%; P = .05]). Adherence rate below 90% was associated with increased relapse risk (hazard ratio, 3.9; P = .01). Using an adherence rate <90% to define nonadherence, 20.5% of the participants were nonadherers. We identify race-specific determinants of adherence, and define a clinically relevant level of adherence needed to minimize relapse risk in a multiracial cohort of children with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00268528.

Outcome of Children with Standard-Risk T-Lineage Acute Lymphoblastic Leukemia--Comparison among Different Treatment Strategies.

BACKGROUND: Children with T-lineage acute lymphoblastic leukemia ALL (T-ALL) historically have had inferior outcomes compared with the children with precursor-B ALL (B-ALL). After 1995, the Children's Cancer Group (CCG) treated patients with B- and T-ALL according to the National Cancer Institute (NCI) risk criteria, basing risk stratification on age and white blood cell (WBC) count regardless of immunophenotype. The Pediatric Oncology Group (POG) treated all the patients with T-ALL on separate, generally more intensive protocols than those used to treat the patients with B-ALL. PROCEDURE: We compared the outcomes of children with T-ALL and NCI standard-risk (SR) criteria treated on CCG and POG trials between 1996 and 2005. CCG SR-ALL 1952 and 1991 enrolled 80 and 86 patients with T-ALL, respectively, utilizing a reduced intensity Berlin-Frankfurt-Münster backbone. Treatment was intensified for slow early responders and only patients with overt central nervous system leukemia received cranial irradiation. Eighty-four patients with T-ALL and SR features were enrolled on POG 9404 comprising more intensive therapy with all patients receiving cranial irradiation. RESULTS: The 7-year event-free survival (EFS) for patients with SR T-ALL on CCG 1952, CCG 1991, and POG 9404 were 74.1 ± 5.8%, 81.8 ± 5.3%, and 84.2 ± 4.3%, respectively (P = 0.18). Overall 7-year survivals were 86.1 ± 4.6%, 88.3 ± 4.4%, 89.1 ± 3.6%, respectively (P = 0.84). CONCLUSIONS: Comparable high rates of EFS and long-term survival were achieved with all three regimens, with the CCG regimens utilizing a less intensive chemotherapy backbone without prophylactic cranial irradiation for patients with SR T-ALL.

Prolonged Response in Patient With Multiply Relapsed B-cell Acute Lymphoblastic Leukemia and Monosomy-7 to Bortezomib, Lenalidomide, and Dexamethasone.

Isolated monosomy-7, a rare cytogenetic abnormality in patients with pediatric acute lymphoblastic leukemia (ALL), portends a worse prognosis. Despite improvements in treatment, outcomes for patients with relapsed ALL remain poor. Novel treatments adopted from the B-cell malignancy multiple myeloma may have a role in treatment of ALL. Bortezomib is one such agent currently in phase III trials for B and T ALL. This study presents a patient with B-cell ALL and monosomy-7 who relapsed off therapy. The combination of bortezomib, lenalidomide, and dexamethasone was used to attain remission before bone marrow transplant after conventional relapse therapy failed. A recurrence after bone marrow transplant was controlled for a prolonged period with the same therapy. The case supports the hypothesis that bortezomib, lenalidomide, and dexamethasone should be further explored in the treatment of B-cell ALL with monosomy-7.

Survivors of standard risk acute lymphoblastic leukemia do not have increased risk for overweight and obesity compared to non-cancer peers: a report from the Children's Oncology Group.

BACKGROUND: We sought to determine whether survivors of standard risk ALL (SR-ALL) treated without cranial radiation have increased risk for obesity by assessing changes in body mass index (BMI) during and after treatment; identifying contributing patient and treatment factors; comparing rates of overweight/obese to national health data. PROCEDURE: Eligibility for this retrospective cohort study included: (i) previous enrollment on legacy therapy trials CCG1922 or CCG1952; (ii) continuous first remission; and (iii) age at follow-up evaluation of 6-16.99 years. Height and weight from diagnosis, consolidation, start of maintenance, last cycle of maintenance, and off-therapy were analyzed. RESULTS: The 269 subjects were a median age of 3.5 years at diagnosis and 13.3 years at follow-up. BMI% significantly increased from induction to consolidation (+17.6 ± 1.6%), start of maintenance to end-of-treatment (+3.3 ± 1.6%) and decreased from end-of-treatment to follow-up (-3.5 ± 1.6%,). Higher BMI% at follow-up was associated with higher BMI% at diagnosis (P < 0.0001), but not age at diagnosis, gender, or race. Patients previously randomized to dexamethasone had a stronger association between BMI% at diagnosis and BMI% at follow-up than those who received prednisone (P = 0.0005). At follow-up, 39% of survivors were overweight or obese; the relative risk of overweight/obese was 1.028 (P = 0.738) compared to the general population. CONCLUSIONS: Our study of patients with SR-ALL found a significant increase in BMI% largely during the first month of therapy that is greater with dexamethasone than prednisone. However, after therapy, there was no increased risk of overweight/obese BMI compared to non-cancer peers.

Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study.

Therapy of relapsed pediatric acute lymphoblastic leukemia (ALL) is hampered by low remission rates and high toxicity, especially in second and subsequent relapses. Our phase 1 study, T2005-003, showed that the combination of bortezomib with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin had acceptable toxicity. We report the phase 2 expansion of this combination in patients with relapsed ALL who failed 2-3 previous regimens. Twenty-two patients with relapsed ALL were treated with bortezomib combined with this regimen; their ages ranged from 1 to 22 years, and they had either B-precursor ALL (n = 20) or T-cell ALL (n = 2). Grade 3 peripheral neuropathy developed in 2 (9%) patients. After 3 patients died from bacterial infections, treatment with vancomycin, levofloxacin, and voriconazole prophylaxis resulted in no further infectious mortality in the last 6 patients. Fourteen patients achieved complete remission (CR), and 2 achieved CR without platelet recovery, for an overall 73% response rate, meeting predefined criteria allowing for early closure. B-precursor patients faired best, with 16 of 20 (80%) CR + CR without platelet recovery, whereas the 2 patients with T-cell ALL did not respond. Thus, this combination of bortezomib with chemotherapy is active in B-precursor ALL, and prophylactic antibiotics may be useful in reducing mortality. Bortezomib merits further evaluation in combination therapy in pediatric B-precursor ALL. This study is registered at http://www.clinicaltrials.gov as NCT00440726.

The association between fasting hypoglycemia and methylated mercaptopurine metabolites in children with acute lymphoblastic leukemia.

BACKGROUND: Symptomatic fasting hypoglycemia has been reported as an unusual side effect in patients with acute lymphoblastic leukemia (ALL) on maintenance therapy. We evaluated the relation of the red cell 6-mercaptopurine (6-MP) metabolite 6-methyl-mercaptopurine (6MMP) with hypoglycemia. PROCEDURE: We retrospectively reviewed charts of three patients with ALL and symptomatic hypoglycemia while fasting who were noted to have high levels of 6MMP. All patients had an empiric trial of switching from evening to morning 6-MP administration, and two patients were subsequently switched to twice daily dosing. Patients also received complex carbohydrates at bedtime. RESULTS: Switching 6-MP from evening to morning administration reduced 6MMP levels yet preserved adequate levels of the active metabolite red cell 6-thioguanine nucleotide (6TGN). All patients had decreased hypoglycemic events when changed from evening to morning dosing. Two patients showed a rebound in 6MMP levels with return of hypoglycemic symptoms. Both were then switched to twice daily 6-MP dosing with one having a decrease in 6MMP and hypoglycemic symptoms. CONCLUSIONS: High levels of 6MMP are associated with symptomatic hypoglycemia which may be mitigated by switching to morning or twice daily 6-MP dose administration.

A phase I study of EZN-3042, a novel survivin messenger ribonucleic acid (mRNA) antagonist, administered in combination with chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium.

To address the therapeutic challenges in childhood relapsed ALL, a phase 1 study combining a survivin mRNA antagonist, EZN-3042, with reinduction chemotherapy was developed for pediatric patients with second or greater bone marrow relapses of B-lymphoblastic leukemia. EZN-3042 was administered as a single agent on days -5 and -2 and then in combination with a 4-drug reinduction platform on days 8, 15, 22, and 29. Toxicity and the biological activity of EZN-3042 were assessed. Six patients were enrolled at dose level 1 (EZN-3042 2.5 mg/kg/dose). Two dose-limiting toxicities were observed: 1 patient developed a grade 3 γ-glutamyl transferase elevation and another patient developed a grade 3 gastrointestinal bleeding. Downmodulation of survivin mRNA and protein were assessed after single-agent dosing and decreased expression was observed in 2 of 5 patients with sufficient material for analysis. Although some biological activity was observed, the combination of EZN-3042 with intensive reinduction chemotherapy was not tolerated at a dose that led to consistent downregulation of survivin expression. The trial was terminated following the completion of dose level 1, after further clinical development of this agent was halted.

Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group.

Children's Cancer Group-1991 selected 2 components from the Children's Cancer Group studies shown to be effective in high-risk acute lymphoblastic leukemia and examined them in children with National Cancer Institute standard-risk acute B-precursor lymphoblastic leukemia. These were (1) vincristine and escalating IV methotrexate (MTX) without leucovorin rescue during the interim maintenance (IM) phases and (2) addition of a second delayed intensification (DI) phase. Eligible patients (n = 2078) were randomly assigned to regimens containing either oral (PO) MTX, PO mercaptopurine, dexamethasone, and vincristine or IV MTX during IM phases, and regimens with either single DI or double DI. Five-year event-free survival (EFS) and overall survival for patients on the PO MTX arms were 88.7% ± 1.4% and 96% ± 0.9% versus 92.6% ± 1.2% and 96.5% ± 0.8% for those on the IV MTX arms (P = .009, P = .66). Five-year EFS and overall survival for patients who received single DI were 90.9% ± 1.3% and 97.1% ± 0.8% versus 90.5% ± 1.3% and 95.4% ± 3.8% for those who received double DI (P = .71, P = .12). No advantage was found for a second DI; however, replacement of PO MTX, PO mercaptopurine, vincristine, and dexamethasone during IM with vincristine and escalating IV MTX improved EFS.