Latent Tuberculosis in Hematopoietic Stem Cell Transplantation: Diagnostic and Therapeutic Strategies to Prevent Disease Activation in an Endemic Population.

Latent tuberculosis infection (LTBI) affects one-fourth of the world´s population. Hematopoietic stem cell transplantation (HSCT) recipients are at an elevated risk of developing active tuberculosis infection (ATBI). In this retrospective study of donors and HSCT recipients who underwent transplantation between February 2000 and June 2018, our aim was to determine the prevalence of LTBI and ATBI and to describe diagnostic and therapeutic strategies in an HSCT population in an endemic region. The cohort of 409 participants included 125 allogeneic HSCT (allo-HSCT) recipients, 165 autologous HSCT (auto-HSCT) recipients, and 119 HSCT donors. Patients were evaluated pre-HSCT with tuberculin skin test and thoracic imaging. LTBI was diagnosed in 26.2% of the cohort. Cases represented 20% of the auto-HSCT population, 20% of the allo-HSCT population, and 41.2% of the donor population. Pre-HSCT evaluation to rule out ATBI was performed in 62.6% of the cohort; all results were negative. Isoniazid was administered to 73.3% of those with LTBI. Within subgroups, 91.7% of HSCT recipients and 51% of donors received treatment. The median duration of therapy pre-HSCT was 70 days in recipients and 48 days in donors. The incidence of post-HSCT ATBI was 0 at 1-year follow-up. The incidence of LTBI in our population was higher than expected and still might have been underestimated owing to diagnostic test limitations. The absence of incident ATBI suggests that recipients, as opposed to donors, must receive LTBI treatment. Prevention of infectious complications in the HSCT population should be prioritized to improve clinical outcomes. Prospective data from collaborative working groups is needed to determine the best diagnostic and therapeutic approaches in this vulnerable patient population.

Outcomes and Challenges of Reproductive Health in Hematopoietic Stem Cell Transplantation Survivors.

Long-term therapy-related reproductive health side effects impact the quality of life of hematopoietic stem cell transplantation (HSCT) survivors. In this study, we evaluated the prevalence of gonadal dysfunction (GD) pre- and post-HSCT, analyzed factors associated with GD, and explored rates of fertility assessment (FA) and fertility preservation (FP) in a resource-limited setting. FA and outcomes of patients age ≤45 years undergoing HSCT between June 2000 and May 2018 were collected retrospectively. We included 213 patients with a median age of 26 years. Pre-HSCT FA was performed in 71.8%, with a GD rate of 17%. The rate of GD was not different between the sexes (females, 19.5% versus males, 16.1%; P = .616) and was only associated with increasing age. The rate of cryopreservation in the cohort was 3.3%. Almost one-half (47.7%) of post-HSCT patients completed FA and evidenced an increase in GD rate to 48.9%. Comparing pre-HSCT and post-HSCT GD rates, women had a significant increase (19.5% versus 81.4%; P < .001), whereas men did not (16.1% versus 20.4%; P = .76). These results were confirmed by a multiple imputation analysis accounting for missing data. Female sex, pre-HSCT cytotoxic therapy, myeloablative conditioning, and germ cell tumor (GCT) diagnosis were associated with post-HSCT GD. Reproductive health preservation can be positively impacted when FA and FP are prioritized at the initial diagnosis in HSCT candidates, particularly in women of older age and men with a diagnosis of GCT. The low FP success observed urges implementation of strategies that favor accessibility and improve quality of life of HSCT survivors in low- and middle-income countries.

Isolated Extramedullary Relapse in Acute Lymphoblastic Leukemia: What Can We Do Before and After Transplant?

• Isolated EMR is defined as the presence of clonal blasts in any tissue other than the medullary compartment with a bone marrow evaluation with less than 5% clonal blasts and a full donor chimerism. • Patients with iEMR have shown better survival outcomes when compared to BMR and EMR and in most cases it heralds a systemic relapse. • Risk factors for iEMR include: younger age, history of EMD, poor risk cytogenetics, advanced disease at HSCT, development of GVHD, and non-TBI based conditioning regimens. • Combination therapy, local and systemic, can achieve better remission rates in this subgroup of patients.

Challenges of Treating a Patient With Advanced Prostate Cancer During the COVID-19 Pandemic.

A 78-year-old man had a medical history of hypertension, atrial fibrillation, chronic kidney disease, and metastatic castration-resistant prostate cancer (CRPC). He had progressed to first-line therapy for CRPC with abiraterone plus androgen-deprivation therapy (ADT) and as second-line therapy he was being treated with docetaxel, with biochemical progression in his last prostate specific antigen measurement. He was admitted to the hospital on April 2020, in the middle of the coronavirus disease 2019 (COVID-19) pandemic, because of painful bone lesions and deterioration of renal function.

Bispecific Antibodies in Hematologic Malignancies: When, to Whom, and How Should Be Best Used?

PURPOSE OF REVIEW: The purpose of this review is to discuss the current recommendations for the use of bispecific antibodies (bsAb) in hematologic malignancies and explore the future in this field. RECENT FINDINGS: Bispecific antibodies are molecules able to target two different antigen-binding sites: one towards a tumor antigen and another to activate a cytotoxic cell. Phase II/III trials on blinatumomab for acute lymphoblastic leukemia (ALL) have demonstrated its efficacy for treating minimal residual disease (MRD+) and relapsed refractory (r/r) Philadelphia positive (Ph+) and negative (Ph-) ALL in adults and children. Currently, the only bispecific antibody (bsAb) approved for its use in hematologic malignancies is blinatumomab. However, multiple trials are under development not only to explore blinatumomab's clinical activity in other neoplasia, such as lymphoma or multiple myeloma, but also to develop new molecules against different antigens.

Hematopoietic Stem Cell Transplantation for Adult Philadelphia-Negative Acute Lymphoblastic Leukemia in the First Complete Remission in the Era of Minimal Residual Disease.

PURPOSE OF REVIEW: The purpose of this review is to discuss the potential role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for Philadelphia-negative (Ph-) adult acute lymphoblastic leukemia (ALL) in first complete remission (CR1) in the era of minimal residual disease (MRD). RECENT FINDINGS: Allo-HSCT continues to have a role in the therapy of a selected group of high-risk adult patients with ALL in CR1. Although the clinical significance of MRD has been studied less extensively in adults with ALL than in children, recent studies support its role as the strongest prognostic factor that can identify patients that are unlikely to be cured by standard chemotherapy and benefit from undergoing allo-HSCT. In addition, MRD status both pre- and post-HSCT has been found to correlate directly with the risk of relapse. Currently, the clinical challenge consists on applying MRD and molecular failure to integrate novel agents and immunotherapy to lower MRD before allo-HSCT and to modulate the graft versus leukemia (GVL) effect after transplant.

Extramedullary disease at diagnosis of AML does not influence outcome of patients undergoing allogeneic hematopoietic cell transplant in CR1.

OBJECTIVE: Extramedullary disease (EMD) at diagnosis of acute myeloid leukemia (AML) has been associated with increased risk of relapse and worse outcomes post-chemotherapy. This study sought to investigate the association of EMD with outcomes following allogeneic hematopoietic cell transplantation (allo-HCT). METHODS: This single-center retrospective study investigated the impact of EMD at diagnosis on the outcome of patients transplanted for AML in first complete remission (CR1). The study included 303 consecutive patients with AML transplanted in CR1, median age 51 years (range 18-71). RESULTS: EMD at diagnosis was documented in 39 patients (13%), either histologically (26 patients) or clinically/radiologically (13 patients). Among the 39 EMD patients, 16 had CNS disease, seven had gingival infiltration, and five had leukemia cutis. On univariate analysis, EMD had no significant impact on survival, with a 3-year OS of 55% (95% CI 38-69) compared to 48% for the non-EMD group (95% CI 42%-55%) (P=.84). Likewise, 3-year CIR was 18% vs 19% (P=.86) and 3-year NRM was 26% vs 33% (P=.83) for EMD vs non-EMD groups, respectively. Multivariate analysis confirmed these results. CONCLUSIONS: We conclude that EMD at diagnosis of AML does not seem to influence outcomes following allo-HCT performed in CR1.

Complement gene variant effect on relapse of complement-mediated thrombotic microangiopathy after eculizumab cessation.

Eculizumab is effective for complement-mediated thrombotic microangiopathy (CM-TMA), also known as atypical hemolytic uremic syndrome. Although lifelong therapy had been suggested, discontinuation does not universally lead to relapse. Comprehensive data evaluating risk factors for recurrence following discontinuation are limited. Our aim was to systematically review available literature assessing the role of complement genetic variants in this setting. Reports on CM-TMA and eculizumab withdrawal published before 1 January 2021, were included. Key reasons for patient exclusion were no follow-up after drug withdrawal and patients lacking complement genetic testing. Two-hundred eighty patients from 40 publications were included. Median age was 28 years, and 25 patients had a known history of renal transplant. Complement genetic variants were identified in 60%, most commonly in CFH (n = 59) and MCP/CD46 (n = 38). Of patients with a complement gene variant, 51.3% had ≥1 likely pathogenic/pathogenic variant whereas the remaining had variants of uncertain significance (VUS). Overall relapse rate after therapy discontinuation was 29.6%. Relapse rate was highest among patients with CFH variants and MCP/CD46 variants in canonical splice regions. VUS (P < .001) and likely pathogenic/pathogenic variants (P < .001) were associated with increased relapse. Presence of a renal allograft (P = .009); decreasing age (P = .029); and detection of variants in CFH (P < .001), MCP/CD46 (P < .001), or C3 (P < .001) were all independently associated with relapse after eculizumab discontinuation. Eculizumab discontinuation is appropriate in specific patients with CM-TMA. Caution should be exerted when attempting such a strategy in patients with high risk of recurrence, including a subgroup of patients with MCP/CD46 variants.

Myeloablative Dose of Busulfan and Fludarabine Combined with In Vivo T Cell Depletion Is Safe and Effective Conditioning for Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative strategy for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The prediction of transplantation-related mortality (TRM) using the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score and an arbitrary upper age limit of 55 years for administering myeloablative conditioning (MAC) are common strategies to ensure a safe procedure. The use of reduced-toxicity conditioning regimens is an additional approach to providing safe and effective myeloablation. Herein we report the outcome of AML and MDS patients conditioned with fludarabine and a myeloablative dose of busulfan (FB4) stratified by age and HCT-CI score. The primary objective was overall survival (OS) for patients age ≥55 years. Secondary objectives were total OS, TRM, graft-versus-host disease (GVHD), and GVHD, relapse-free survival (GRFS). The 2 year OS was 72% in patients age <55 and 51% in patients age ≥55. In patients age ≥55 with an HCT-CI <2, the estimated 2 year OS was 64%, with median OS not reached. In those with HCT-CI ≥2, the 2-year OS was 43%, with a median OS of 14 months. The total cumulative incidence of relapse was 30% regardless of age or HCT-CI score. FB4 conditioning regimen offers a high rate of prolonged remission with a relapse rate similar to that reported in previous studies. These positive outcomes suggest that this conditioning platform can be offered to patients age ≥55 years in the absence of comorbidities, and that age should not be the sole determinant of conditioning intensity.

Acute Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The Good, the Bad, and the Ugly of Isolated Extramedullary Relapse in a Latin American Population.

Hematopoietic stem cell transplantation (HSCT) is an effective therapy for acute leukemia (AL). Relapse represents the main cause of mortality. Isolated extramedullary relapse (iEMR) is atypical and has been related to better outcomes. Here we describe the clinical characteristics and outcomes of AL relapse after HSCT in our study population and analyze the impacts of different types of relapse on survival outcomes. This retrospective, multicenter study included 124 patients age ≥15 years with AL who underwent HSCT between 2004 and 2019. At diagnosis, 66.1% of the patients had lymphocytic AL, 19.7% presented with high-risk features, and 18.5% had extramedullary disease (EMD). At HSCT, 83.1% of the patients were in complete remission (CR), and 44.8% had negative measurable residual disease (MRD). The vast majority of donors were related (96%), including 48.4% HLA-matched and 47.6% haploidentical. Myeloablative conditioning was provided to 80.6% of patients. The median overall survival (OS) was 15 months (95% confidence interval [CI] 9.9 to 20.1 months). Factors associated with improved OS were adolescent and young adult (AYA) patient (P = .035), first or second CR (P = .026), and chronic graft-versus-host disease (GVHD) (P < .001). Acute GVHD grade III-IV (P = .009) was associated with increased mortality. The median relapse-free survival was 13 months (95% CI, 7.17 to 18.8 months); early disease status (P = .017) and chronic GVHD (P < .001) had protective roles. Sixty-eight patients (55%) relapsed after HSCT, with a median time to relapse of 6 months (95% CI, 3.6 to 8.4 months). iEMR was reported in 16 patients (23.5%). The most commonly involved extramedullary sites were the central nervous system and skin. Compared to patients with bone marrow relapse, all patients with iEMR had a diagnosis of acute lymphoid leukemia (P = .008), and 93.8% belonged to the AYA group; regarding pre-HSCT characteristics, iEMR patients had higher rates of negative MRD (P = .06) and a history of EMD (P = .009). Seventy-seven percent of relapsed patients received additional treatment with curative intent. The median OS after relapse (OSr) was 4 months (95% CI, 2.6 to 5.4 months). Factors related to increased OSr included lymphoid phenotype (P = .03), iEMR (P = .0042), late relapse (≥6 months) (P = .014), receipt of systemic therapy including second HSCT (P < .001), and response to therapy (P < .001). Rates of relapse and iEMR were higher than those previously reported in other studies. Advanced disease, reduced-intensity conditioning, and a diminished graft-versus-leukemia effect were factors influencing these findings. At relapse, presenting with iEMR after 6 months and receiving intensive therapy with adequate response were associated with better outcomes. Our results strongly suggest that a personalized approach to treating patients with HSCT is needed to counterbalance specific adverse factors and can positively impact clinical outcomes.

HIV-positive patients presenting with peripheral blood cytopenias: is bone marrow assessment a priority?

INTRODUCTION: Hematologic abnormalities are frequent among persons living with HIV (PLWH). The bone marrow aspirate (BMA) and biopsy (BMB) are commonly performed in the diagnostic approach of patients with unexplained cytopenias. Changes in antiretrovirals, supportive therapy and increased life expectancy have modified the distribution and etiology of cytopenias, questioning their use. Our aim was to analyze the diagnostic yield of BMA, BMB and marrow cultures for the evaluation of cytopenias in PLWH. METHODS: This was a retrospective cohort of ≥ 18-year-old PLWH undergoing bone marrow assessment (MA) for the evaluation of cytopenias between January 2002 and December 2015. RESULTS: A total of 236 cytopenic events were analyzed, 47.9% being PLWH who had a longstanding diagnosis (≥ 1 year). Adherence to antiretrovirals was 63.5%. Anemia was seen in 91.9% and pancytopenia in 39%. Common presentations included fever (52.1%), weight loss (42.8%) and adenopathies (28.8%). Median days from detection to MA was 5 (0 - 63 days). Most common etiologies were non-HIV infectious diseases (31.4%) and benign/malignant hematologic diseases (26.3%). The diagnostic yield was 16.1% for BMA, 20.3% for BMB, 30.5% for both and 35.6% when cultures were added. Patients most likely to have conclusive MA were those with moderate/severe thrombocytopenia (p = 0.007). Fever, splenomegaly, and low CD4+ counts were associated with infectious etiologies, while hematologic diagnoses were related to the presence of adenopathies. CONCLUSION: As a minimally invasive intervention, the MA has a high yield for identifying the etiology of cytopenic events in PLWH, being conclusive in one in three patients. Early performance could lead to prompt diagnosis and timely therapy initiation.

Global Oncology Authorship and Readership Patterns.

PURPOSE: Global Oncology is the movement to improve equitable access to cancer control and care, recognizing challenges because of economic and social factors between high-, middle-, and low-income countries (HIC, MIC, and LIC, respectively). The JCO Global Oncology (JCO GO) is a major platform dedicated to publishing peer-reviewed research relevant to populations with limited resources. To assess the success of its goals of encouraging global interaction and increasing MIC and LIC engagement, we analyzed authorship and readership patterns. METHODS: Metadata of logged views between January 1, 2018, and June 30, 2019, of articles published in 2018 by JCO GO were identified using Google Analytics. The country of origin of each author and those who accessed the journal were categorized according to the 2019 income group World Bank Classification (WBC). RESULTS: One hundred thirty-two articles were published in JCO GO in 2018. Corresponding authors came from 34 nations: 35% HIC, 47% MIC, and 18% LIC. The top publishing countries were the United States, India, Brazil, Mexico, and Nigeria. Article authors were solely from within one WBC group in 41% (23% HIC, 16% MIC, and 2% LIC). In those with mixed-WBC authorship origins, collaborations were 42% HIC + MIC, 11% HIC + LIC, and 6% HIC + MIC + LIC, but none with MIC + LIC. Regarding viewing, 87,860 views originated from 180 countries (82% of the WBC list): 35% HIC, 51% MIC, and 14% LIC. The most common accessing nations were the United States, India, the United Kingdom, Brazil, and Ethiopia. CONCLUSION: More than half of JCO GO's authorship comes from mixed WBC groups, with viewership extending to most of the world's nations. Areas to address are low level of LIC corresponding authors, few papers from authors across all WBC groups, no publications from MIC + LIC collaborations, and a low percentage of readership by LIC. These data provide focus to target interventions aimed at reducing the academic segregation of LIC and improving interactions across all WBC countries.

Induction-related mortality in adolescents and young adults with acute lymphoblastic leukemia in a resource-limited setting: do treatment-related complications create more impact than disease biology?

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a malignant clonal bone marrow disorder with a high mortality rate during the initial therapy. This retrospective study aimed to describe and analyze the risk factors and causes of induction-related mortality (IRM) in an adolescent and adult ALL population treated in a low- and middle-income country. METHODS: From 2009 to 2016, a total of 167 patients were included, of which 50.9% were male with a median age of 28 years. B-immunophenotype represented 97.6%, and high-risk cytogenetics were present in 23.3%. During induction therapy, 91% had at least 1 complication, most of which were infectious, with an IRM of 12%. RESULTS: Factors associated with increased mortality rate were central nervous system (CNS) status [CNS-3: hazard ratio (HR) 3.029; 95% confidence interval (CI), 0.79‒11.49; P =0.103 and CNS-2: HR, 9.98; 95% CI, 2.65‒37.65; P =0.001] and dialysis requirement (HR, 9.15; 95% CI, 2.44‒34.34; P =0.001). CONCLUSION: Our study confirms that ALL patients treated in resource-constrained settings have high rates of IRM, mainly attributed to advanced disease and high tumor burden at diagnosis.

Hematopoietic stem cell transplantation activity in Mexico during the COVID19 pandemic: on the way to recovery.

OBJECTIVE: To analyze the number of HSCTs performed in 2019 vs. 2020 and report the status of transplant centers (TCs) during and a year after the COVID-19 pandemic. METHODS: We performed a comprehensive cross-sectional nationwide study including active TCs interrogating HSCT activity from 2019 through September 2021. An electronic survey was sent to TCs and consisted of items regarding the number and characteristics of procedures performed and were compared yearly. Changes to their institutions' transplant policies and practices during the COVID19 pandemic were also documented. Fifty centers were invited to participate, 33 responded. RESULTS: Most TCs were part of the public health system (63.7%). Almost half are in the country's capital, Mexico City (45.5%). Most centers performed <10 procedures per year. The number of HSCTs decreased from 835 in 2019-505 in 2020 (p < .001), representing a 40% reduction in transplant activity. The monthly transplant rate in 2021 increased to 58.3, compared to 42 in 2020 and close to 69.5 in 2019 (p < .001). All types of HSCTs decreased excluding haploidentical transplants. All institutions treated patients with COVID19, and over two-thirds experienced some form of hospital reconversion. Transplant activity stopped completely in 23 TCs (70%) during the pandemic with a median closure duration of 9.9 months (range, 1-21). In 2021, 9.1% of TCs remained closed, all of them in the public setting. CONCLUSION(S): The limited transplant activity in Mexico decreased significantly during the pandemic but is recovering and nearly in pre-pandemic levels.

Impact of Socioeconomic Characteristics and Comorbidities on Therapy Initiation and Outcomes of Newly Diagnosed Multiple Myeloma: Real-World Data From a Resource-Constrained Setting.

BACKGROUND: Outcomes of newly diagnosed multiple myeloma (NDMM) in developing regions have not paralleled those in developed settings. Economic disadvantage, comorbidities, and aggressive disease behavior play competing roles on defining outcomes. Our aim was to analyze the impact of socioeconomic characteristics and comorbidities on therapy initiation, drug selection, and survival outcomes of NDMM in a resource-constrained setting. PATIENTS AND METHODS: This retrospective single-center cohort included ≥ 18-year-old NDMM patients from January 2006 to December 2018. RESULTS: A total of 245 patients were included with a median age of 62 years, Eastern Cooperative Oncology Group performance status ≤ 2 in 70.2%, International Staging System score ≥ 2 in 89.4%, and high-risk disease in 31.6%. Comorbidities were reported in 69.4%, and Charlson comorbidity index (CCI) was ≥ 2 in 64.1%. A total of 87.4% (n = 214) received thalidomide-, alkylating-, and bortezomib-based induction in 67.8%, 18.2%, and 13.1%. Patient-related factors including performance status, comorbidities, and CCI, but not myeloma-related factors, were associated with a decreased likelihood of initiating induction therapy. On multivariate analysis, CCI ≥ 2 remained statistically significant (odds ratio, 5.81; P = .005). Overall survival was 44 months. Although both patient- and myeloma-related factors were associated with a decreased overall survival, only International Staging System score > 2 (hazard ratio, 3.53; P = .004) and induction without bortezomib-based regimens (hazard ratio, 4.45; P < .001) were statistically significant on multivariate analysis. CONCLUSION: Myeloma- and treatment-related factors are the main determinants of survival in NDMM induction-eligible patients. Patient-related factors play a pivotal role determining access to therapy and survival outcomes. Comorbidity index and performance status were determinant on defining therapy initiation in this real-world population, which emphasizes the need to improve health baseline conditions in resource-constrained settings.

Access to Palliative Care Services and Clinical Outcomes of Patients With Solid Malignancy-Associated Myelophthisis in a Resource-Limited Setting.

BACKGROUND: Myelophthisis (MPT) has been associated with a dreadful prognosis. Patients' access to palliative care (PC) and factors influencing its clinical outcomes are poorly described. Our aim was to analyze the impact of patient- and disease-specific characteristics on survival of patients with MPT and describe their use of PC in a resource-limited setting. METHODS: Retrospective study including patients with solid tumor MPT, diagnosed between 1996 and 2018. RESULTS: Seventy patients (median 58 years) were included. 58% were synchronously diagnosed with MPT at time of primary tumor diagnosis. Most common oncologic diagnoses were prostate (25.7%), gastrointestinal (20%), and breast (18.6%) neoplasms. Median overall survival (OS) was 1.9 months. Primaries other than prostate, breast, and lung (HR 1.37, 95% CI 1.15 - 1.8; p = 0.02) and transfusion requirements (HR 2.8, 95% CI 1.01 - 7.9; p = 0.04) were independently associated with decreased OS. Administration of multiple systemic therapeutic interventions (HR 0.15, 95% CI 0.06 - 0.39; p = 0.01) was the sole factor improving OS. Assessment by PC was pursued in 51.4% of patients. The median number of consults per patient was two, with no difference in assessment rate or consult number across different primaries (P = 0.96). Four cases of palliative sedation were reported, all performed by the primary care team. CONCLUSION: MPT is highly heterogeneous and risk stratification to optimize the use of therapeutic interventions in unison with palliative interventions is needed to maximize efforts toward improving patient quality of life. There is an alarming need of PC services in the multidisciplinary management of patients within developing regions.