Lesson learned in pediatric haploidentical transplantation in a low-resource environment: delivering melphalan IV and using low dose radiation reduce graft failure.

Objectives: Primary graft failure (pGF) after hematopoietic stem-cell transplant is associated with considerable morbidity and mortality. The incidence in haplo-HSCT has been reported to be between 0% and 30%. In 2018, we identified a pGF incidence of 35% in our pediatric haplo-HSCT recipients with hematologic malignancies, which motivated us to enact changes to the conditioning regimen.Methods: We performed a single-center prospective, pre-post study of consecutive patients under 16 years with hematologic malignancies, from January 2015 to December 2022 who received a haplo-HSCT. Twenty-six pediatric patients received a haplo-HSCT before September 2018 (G1) and 36 patients after (G2). The main conditioning regimen for G1 was myeloablative with Flu/Cy/Bu, and for G2 the main regimen was reduced intensity Flu/Cy/Mel/TBI2.Results: Nine patients (35%) in G1 had primary graft failure, while in G2 there were no patients with pGF. The median follow-up for G1 was 15.9 months, and for G2 was 24.8 months, with an estimated overall survival at 12 months of 63% (95% CI 47-76) versus 85% (95% CI 73-93), and at 24 months of 47% (95% CI 31-64) versus 70% (95% CI 54-82) respectively (p = .007).Conclusion: After September 2018 conditioning regimen modifications were implemented with the objective of reducing primary failure, consisting mainly of switching from busulfan to melphalan as the alkylating agent of choice, and adding, when clinically possible TBI. Primary failure has been significantly reduced in our institution since then.

Point of care thoracic ultrasound versus chest computed tomography in the approach of febrile neutropenia patients: A diagnostic accuracy cohort study.

Single-center prospective cohort diagnostic accuracy study. Our study aimed to evaluate the accuracy and reproducibility of Thoracic Ultrasound (TUS) in detecting pulmonary pathology in immunosuppressed patients. We conducted a single-center prospective study. Consecutive patients with febrile neutropenia who underwent CT (Computerized Tomography) underwent TUS evaluation within 24h of CT. Both studies were performed by an expert who was blinded to the clinical information and results of the alternative imaging modalities. 34 patients met the inclusion criteria. The median age was 39.9 years (±17 standard deviation). TUS as a diagnostic test had a sensitivity of 92.9% and specificity of 83.3%, negative predictive value of 71.4%, and positive predictive value of 96.3%. Substantial between-method agreement was demonstrated with a kappa of 0.71 (P = .001) between the TUS and chest CT findings. We obtained a kappa of 1 (P = .001) for the final diagnosis of Pleural Effusion (PE). We concluded that TUS is a promising screening test for immunocompromised individuals. The results showed good diagnostic performance of TUS compared to CT for the detection of pulmonary findings highly suggestive of pathology with high accuracy and reproducibility.

Graft-versus-host disease after an outpatient peripheral blood hematopoietic cell transplant using reduced-intensity conditioning: a single-center LATAM experience.

BACKGROUND: HLA compatibility predicts allogeneic hematopoietic cell transplant (allo-HCT) and graft-versus-host disease (GvHD) outcomes. There is insufficient information regarding GvHD outcomes for outpatient HLA-identical and haploidentical-HCT employing reduced-intensity conditioning (RIC). RESEARCH DESIGN AND METHODS: We compare GvHD outcomes between donor types and report risk factors associated with GvHD. Stem cell source was T-cell replete peripheral blood. GvHD prophylaxis was post-transplant cyclophosphamide (PT-CY), mycophenolic acid, and calcineurin inhibitors for haploidentical (n = 107) and oral cyclosporine (CsA) plus methotrexate i.v. for HLA-identical (n = 89) recipients. RESULTS: One hundred and ninety-six HCT transplant patients were included. aGvHD and cGvHD frequency were similar between HCT types. aGvHD severity was comparable, but severe cGvHD was less frequent in the haploidentical group (p = .011). One-hundred-day cumulative incidence (CI) of aGvHD for haploidentical and HLA-identical was 31% and 33% (p = .84); 2-year CI of cGvHD was 32% and 38% (p = .6), respectively. Haploidentical recipients had less steroid-refractory cGvHD (p = .043). Patients with cGvHD had less 2-year relapse (p = .003); both aGvHD and cGvHD conferred higher OS (p = .010 and p = .001), respectively. Male sex was protective for steroid-refractory cGvHD (p = .028). CONCLUSIONS: Acute and chronic GvHD rates were comparable between HLA-identical and haploidentical transplant groups. cGvHD severity was lower in the haploidentical group.

The consequences of delayed diagnosis and treatment in persons with multiple sclerosis given autologous hematopoietic stem cell transplantation.

OBJECTIVES: We have analyzed the association of delayed both diagnosis and treatment of persons with MS with the long-term results of patients given aHSCT. METHODS: Patients with MS referred to the HSCT-Mexico program were included in the study; in 103, detailed pre- and post-transplant evolution could be recorded. Two groups of patients were analyzed according to the time of evolution between the onset of symptoms and the definite diagnosis of MS: more than 8 months (delayed diagnosis, DD), or less than 8 months (non-delayed diagnosis, NDD). The progression of MS was assessed by changes in the expanded disability status scale (EDSS). RESULTS: The time elapsed between the onset of symptoms and the correct diagnosis was lower for the NDD group (1.55 vs. 35.87 months, p<0.05). Both groups of patients showed a similar EDSS score at diagnosis (1.5 vs. 1.5); however, the EDSS at the time of the transplant was higher in the DD group (4.5 vs. 3.0, p=0.3) and the response of the EDSS score to the transplant was significantly better for the NDD group, the last EDSS scores being 2.5 vs. 4.25 (p=0.03). Both groups of patients responded to aHSCT by diminishing the EDSS, but the response was significantly better in the NDD group. CONCLUSIONS: These data indicate that both the pre-transplant progression of the disease and the response to aHSCT were significantly worse in the DD group. An early diagnosis and an early aHSCT intervention are critical for a good prognosis, in terms of lowering and stabilizing the motor disability in MS patients given autografts.

Patients Age 40 Years and Younger With Multiple Myeloma Have the Same Prognosis as Older Patients: An Analysis of Real-World Patients' Evidence From Latin America.

PURPOSE: Multiple myeloma (MM) is a highly heterogeneous, incurable disease most frequently diagnosed in the elderly. Therefore, data on clinical characteristics and outcomes in the very young population are scarce. PATIENTS AND METHODS: We analyzed clinical characteristics, response to treatment, and survival in 103 patients with newly diagnosed MM age 40 years or younger compared with 256 patients age 41-50 years and 957 patients age 51 years or older. RESULTS: There were no statistical differences in sex, isotype, International Scoring System, renal involvement, hypercalcemia, anemia, dialysis, bony lesions, extramedullary disease, and lactate dehydrogenase (LDH). The most used regimen in young patients was cyclophosphamide, bortezomib, dexamethasone, followed by cyclophosphamide, thalidomide, dexamethasone and bortezomib, thalidomide, dexamethasone. Of the patients age 40 years or younger, only 53% received autologous stem-cell transplant (ASCT) and 71.1% received maintenance. There were no differences in overall survival (OS) in the three patient cohorts. In the multivariate analysis, only high LDH, high cytogenetic risk, and ASCT were statistically associated with survival. CONCLUSION: In conclusion, younger patients with MM in Latin America have similar clinical characteristics, responses, and OS compared with the elderly.

Lactate dehydrogenase as a hematopoietic stem cell mobilization biomarker in autologous transplantation

ABSTRACT Introduction: Pre-apheresis peripheral blood CD34+ cell count (PBCD34+) is the most important predictor of good cell mobilization before hematopoietic stem cell transplantation, albeit flow cytometry is not always immediately available. Identification of surrogate markers can be useful. The CD34+ cells proliferate after mobilization, resulting in elevated lactate dehydrogenase (LDH) activity and correlating with the PBCD34+ count. Objective: To determine the LDH cut-off value at which adequate CD34+ cell mobilization is achieved and its diagnostic yield. Materials and methods: A total of 103 patients who received an autologous stem cell transplantation (ASCT) between January 2015 and January 2020 were included. Demographic and laboratory characteristics were obtained, including complete blood count, pre-apheresis PBCD34+ and LDH levels. Receiver operating characteristic (ROC) curves were performed to identify the optimal serum LDH activity cut-off points for ≥ 2 and ≥ 4 × 106 cells/kg post-mobilization CD34+ count and their diagnostic yield. Results: A post-mobilization serum LDH cut-off value of 462 U/L yielded a sensitivity (Se) = 86.8% (positive predictive value [PPV] = 72.7%), a pre- and post-mobilization serum LDH difference cut-off value of 387 U/L, an Se = 45.7% (PPV = 97%) and an LDH ratio of 2.46, with an Se = 47.1% (PPV = 97%) for an optimal mobilization count (CD34+ ≥ 4 × 106). Conclusion: The LDH measurement represents a fast and affordable way to predict PBCD34+ mobilization in cases where flow cytometry is not immediately available. According to the LDH diagnostic yield, it could be used as a surrogate marker in transplant centers, supporting the CD34+ count, which remains the gold standard.

Low-dose rituximab in steroid-refractory chronic graft-versus-host disease.

BACKGROUND: Chronic graft-versus-host disease (cGvHD) is a major complication that puts patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) at risk of death or infection. Currently, there is no gold standard for the first-line treatment of patients who do not respond to steroids, and there are several therapeutic options being evaluated in clinical trials for this disease to be used even in the first-line treatment for GvHD. There is evidence of the benefit of rituximab, an anti-CD20 antibody, at a standard dose of 375 mg/m2 weekly in the treatment of steroid-refractory chronic graft-versus disease (SR-cGvHD). OBJECTIVE: To demonstrate the safety and efficacy of low-dose rituximab in a middle-income center in northeastern Mexico STUDY DESIGN: We report the experience of 26 patients with chronic graft-versus-graft disease who received low-dose rituximab (100 mg weekly for 4 weeks). We utilized the advances in the National Institutes of Health (NIH) criteria for diagnosis, scoring, trial design, and assessment of treatment response. RESULTS: We obtained a 5-year overall survival of 23.6%, including four patients with complete response. The 1-year event-free survival was 70% for patients with rituximab. During the treatment, there were 3 hospitalizations, and the causes were: immune thrombocytopenia, a parapneumonic effusion, and a cerebral vascular event. The median length of hospital stay was twelve days. CONCLUSION: A low dose of rituximab is an available and cost-effective option for patients with steroid-refractory cGvHD.

Anti-Hla Donor-Specific Antibodies Are Associated to Infection and Not to the Engraftment Rate in Outpatient Haploidentical Hematopoietic Cell Transplantation.

Background: Recipients of a related haploidentical stem cell transplant (haplo-SCT) can have preformed antibodies to HLA donor's antigens. Objective: The aim of the study was to evaluate the engraftment rate and major clinical associations of anti-HLA donor-specific antibodies (DSA) at two mean fluorescence intensity (MFI) thresholds in recipients of an outpatient haplo-SCT. Methods: Seventy haplo-HCT recipients were analyzed. A virtual crossmatch was performed using the donor HLA typing and the recipient's anti-HLA DSA test results. Data for anti-HLA-A, -B, -C, and -DR were analyzed. Recipients with DSA ≥ 500 MFI were considered positive, and those with < 500 were considered negative; the same was adopted for MFI ≥ 1000. Results: Post-transplant infection was higher in recipients with DSA ≥ 500 MFI (84.6%, p = 0.041). First-year mortality was higher in DSA-positive patients ≥ 500 MFI, p = 0.004, and DSA ≥ 1000 MFI, p = 0.022, than in DSA-negative recipients. Graft failure in the first 100 days was not associated with DSA ≥ 500 or ≥ 1000 MFI. There was no difference in acute (a-GVHD) or chronic (c-GVHD) graft versus host disease between DSA-positive and negative patients. Conclusions: There was no association of anti-HLA DSA at MFI ≥ 500 and ≥ 1000 with graft failure, however, increased infection and 1st-year mortality were documented in related haplo-HCT at the MFI cutoffs studied.

Comparison of CD4+/CD8+ Lymphocytic Subpopulations Pre- and Post-Antituberculosis Treatment in Patients with Diabetes and Tuberculosis.

Is there a CD4+ and CD8+ immunity alteration in patients with pulmonary tuberculosis (TB) and diabetes (DM) that does not recover after antituberculosis treatment? This prospective comparative study evaluated CD4+ and CD8+ lymphocytic subpopulations and antituberculosis antibodies in patients with diabetes and tuberculosis (TB-DM), before and after antituberculosis treatment. CD4+ T cell counts were lower in patients with TB-DM compared to those with only TB or only DM, and these levels remained low even after two months of anti-TB treatment. Regarding the CD8+ T cell analysis, we identified higher blood values in the DM-only group, which may be explained by the high prevalence of latent tuberculosis (LTBI) in patients with DM. IgM antituberculosis antibodies levels were elevated in patients with only TB at baseline, and 2 months post-anti-TB treatment, IgG did not express any relevant alterations. Our results suggest an alteration in CD4+ immunity in patients with TB-DM that did not normalize after antituberculosis treatment.

Long-Term Efficacy of High-Dose Imatinib in Hispanic Patients Without Access to Second-Generation Tyrosine Kinase Inhibitors Treated in LATAM Centers.

BACKGROUND: While second-generation tyrosine kinase inhibitors (TKI) revolutionized treatment for patients with chronic myeloid leukemia (CML) who developed a suboptimal response to imatinib, many patients in developing countries are fixed to the latter due to socioeconomic barriers. Despite this scenario, scarce information is available to evaluate the clinical prognosis of these patients. METHODS: We conducted a retrospective cohort analysis to compare the overall mortality of patients with CML who developed a suboptimal response to a standard dose of imatinib and were treated with either high-dose imatinib or a second-generation TKI. We created a marginal structural model with inverse probability weighting and stabilized weights. Our primary outcome was overall survival (OS) at 150 months. Our secondary outcomes were disease-free survival (DFS) at 150 months and adverse events. RESULTS: The cohort included 148 patients, of which 32 received high-dose imatinib and 116 a second-generation TKI. No difference was found in the 150-month overall survival risk (RR: 95% CI 0.91, 0.55-1.95, P-value = .77; RD: -0.04, -0.3 to 0.21, P-value = .78) and disease-free survival (RR: 1.02, 95% CI 0.53-2.71, P-value = .96; RD: 0.01, -0.26 to 0.22, P-value = .96). There was also no difference in the incidence of adverse events in either group. CONCLUSION: Ideally, patients who develop a suboptimal response to imatinib should be switched to a second-generation TKI. If impossible, however, our findings suggest that patients treated with high-dose imatinib have a similar overall survival and disease-free survival prognosis to patients receiving a second-generation TKI.

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study.

Data concerning venetoclax and azacitidine (Ven/Aza) as first-line therapy for newly diagnosed acute myeloid leukemia (ND-AML) in candidates for intensive chemotherapy are limited, and outpatient induction regimens in ND-AML have been poorly explored. The enzyme CYP3A4 metabolizes Venetoclax. Conversely, itraconazole is a strong CYP3A4 inhibitor; thus, it produces a 75 % reduction in the dose and cost of venetoclax. This phase 2 trial assessed the feasibility, safety, and efficacy of outpatient induction with venetoclax 100 mg daily from days 1-21, itraconazole 100 mg twice daily from days 1-21, and azacytidine 100 mg subcutaneously, once daily from days 1-7. Fifteen adults with ND-AML were enrolled. The median age was 53 (range 25-73) and twelve (80 %) were considered candidates for intensive chemotherapy. Nine (60 %) subjects started treatment as outpatients,. The first treatment cycle completion in the outpatient setting was achieved in 77.7 %. Early 14-day, 30-day, and 60-day mortality rates were 6.7 %, 13.3 %, and 13.3 %, respectively. Composite CR/CRi after the first and second treatment cycles were 53.9 % and 85.7 %, respectively. Common adverse events included hematological and gastrointestinal toxicities. Outpatient induction with low-dose venetoclax plus itraconazole is feasible, safe, and has acceptable preliminary efficacy in ND-AML patients. This trial was registered in www.clinicaltrials.gov as #NCT05048615.

Assessing the Efficacy of Mitoxantrone and Doxorubicin as Frontline Anthracyclines During Induction Therapy of Newly Diagnosed Acute Promyelocytic Leukemia.

BACKGROUND: Therapeutic advances in acute promyelocytic leukemia (APL) have transformed it into today's most curable form of leukemia. However, recommended agents, including arsenic trioxide, idarubicin, or daunorubicin, are not easily available in low-middle-income countries, where outcomes remain suboptimal. We aimed to assess the efficacy and safety of more accessible anthracyclines. METHODS: We conducted a retrospective cohort study including sixty-one patients diagnosed with APL over a 15-year period. Patients received low-dose all-trans retinoic acid (ATRA, 25 mg/m2) with mitoxantrone or doxorubicin as an induction to remission therapy. Groups were compared using the χ2 and Student's t-tests. Kaplan-Meier analysis was used for survival analyses. RESULTS: Thirty (49.18%) patients received mitoxantrone, and 31 (50.82%) received doxorubicin. The median follow-up was 24.6 months (1-146). Twenty-eight (93.3%) patients achieved complete remission (CR) in the mitoxantrone group and 28 (87.1%) in the doxorubicin group (p=0.103), and the median time to CR was 40 and 31 days, respectively. Mitoxantrone had a 6.7% early mortality rate and a 16.7% relapse rate compared with doxorubicin (3.2% and 32.3%, respectively). No differences were found in survival (p = 0.795), hospitalization days (p = 0.261), or adverse events (p = 0.554). CONCLUSIONS: Using mitoxantrone or doxorubicin as induction therapy in newly diagnosed APL is a safe and adequate alternative with comparable outcomes to first-line agents in scenarios where the latter might not be readily available, such as in low-middle-income countries.

Outcomes and survival predictors of Latin American older adults with acute myeloid leukemia: Data from a single center

ABSTRACT Introduction: Acute myeloid leukemia (AML) is most commonly presented in older adults; however, it appears 10 years earlier in Latin American countries. Clinical evolution in older adults from this populations has not been characterized. We analyzed outcomes and survival predictors. Methods: Patients ≥ 55 years old diagnosed with AML at a hematology referral center from 2005 to 2020 receiving intensive chemotherapy (IC), low-dose cytarabine (LDAC) and best supportive care (BSC) were included. Survival analysis included the Kaplan-Meier and Cox models and the cumulative incidence of relapse (CIR). Results: Seventy-five adults were included and the overall survival (OS) was 4.87, 1.67 and 1.16 months, using IC, LDAC and BSC, respectively. The IC led to a higher OS (p < 0.001) and was a protective factor for early death, at a cost of more days spent hospitalized and more non-fatal treatment complications; non-significant differences were found between the LDAC and BSC. Eight (10.7%) patients underwent hematopoietic cell transplantation, with a higher OS (p = 0.013). Twenty (26.7%) patients achieved complete remission; 12 (60%) relapsed with a 6-month CIR of 57.9% in those < 70 years old vs. 86.5% in those ≥ 70 years old, p = 0.034. Multivariate analysis showed the white blood cell count (WBC) and IC had a significant impact on the patient survival, whereas chronological age and the Charlson comorbidity index (CCI) did not. Conclusion: AML in low-middle income countries demands a different approach; the IC improves survival, even with a high incidence of relapse, and should be offered as first-line treatment. Eligibility criteria should include WBC and a multidimensional evaluation. The age per se and the CCI should not be exclusion criteria to consider IC.

Infection-related mortality after HLA-identical and haploidentical hematopoietic cell transplantation using reduced-intensity conditioning in an outpatient setting.

BACKGROUND: Despite the improvements in supportive care for allogeneic-hematopoietic cell transplantation (allo-HCT) recipients, infectious complications and infection-related mortality (IRM) continue to be a major issue for transplantation centers. METHODS: We herein report the infectious complications and IRM of 107 and 89 patients that underwent haploidentical (haplo-HCT) or HLA-identical HCT at a tertiary referral center during 2013-2020. Patients in the haplo-HCT group received post-transplant cyclophosphamide (PT-Cy), and all received reduced-intensity conditioning regimens. RESULTS: More haplo-HCT recipients presented severe infections in the pre-engraftment period (22.4% vs. 6.7%, p = 0.003). Viral (14.9% vs. 4.5%, p = 0.016) and fungal (12.1% vs. 1.1%, p = 0.003) etiologies were more common in this period in this group. The 100-day and 2-year cumulative incidence of IRM was 15% and 21% for the haplo-HCT and 5.6% and 17% for the HLA-identical group; no significant differences were observed between the groups. Fungal pathogens mainly contributed to IRM (33.3%). Infections were the most common cause of mortality (40/81, 49.4%). There were significant differences in donor/recipient CMV serostatus between transplant groups (0.002). CONCLUSIONS: No differences in IRM were observed based on allo-HCT type, with more haplo-HCT patients suffering from severe infections in the pre-engraftment period. Studies to assess future prevention, diagnostic, and treatment strategies to reduce IRM are warranted.

Pegcetacoplan controls hemolysis in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan is the first C3-targeted therapy approved for adults with PNH (United States), adults with PNH with inadequate response or intolerance to a C5 inhibitor (Australia), and adults with anemia despite C5-targeted therapy for ≥3 months (European Union). PRINCE was a phase 3, randomized, multicenter, open-label, controlled study to evaluate the efficacy and safety of pegcetacoplan vs control (supportive care only; eg, blood transfusions, corticosteroids, and supplements) in complement inhibitor-naive patients with PNH. Eligible adults receiving supportive care only for PNH were randomly assigned and stratified based on their number of transfusions (<4 or ≥4) 12 months before screening. Patients received pegcetacoplan 1080 mg subcutaneously twice weekly or continued supportive care (control) for 26 weeks. Coprimary end points were hemoglobin stabilization (avoidance of >1-g/dL decrease in hemoglobin levels without transfusions) from baseline through week 26 and lactate dehydrogenase (LDH) change at week 26. Overall, 53 patients received pegcetacoplan (n = 35) or control (n = 18). Pegcetacoplan was superior to control for hemoglobin stabilization (pegcetacoplan, 85.7%; control, 0; difference, 73.1%; 95% confidence interval [CI], 57.2-89.0; P < .0001) and change from baseline in LDH (least square mean change: pegcetacoplan, -1870.5 U/L; control, -400.1 U/L; difference, -1470.4 U/L; 95% CI, -2113.4 to -827.3; P < .0001). Pegcetacoplan was well tolerated. No pegcetacoplan-related adverse events were serious, and no new safety signals were observed. Pegcetacoplan rapidly and significantly stabilized hemoglobin and reduced LDH in complement inhibitor-naive patients and had a favorable safety profile. This trial was registered at www.clinicaltrials.gov as NCT04085601.