Relapse and transformation to myelodysplastic syndrome and acute myeloid leukemia following immunosuppressive therapy for aplastic anemia is more common as compared to allogeneic stem cell transplantation with a negative impact on survival.

We studied the incidence of relapse, transformation to myelodysplastic syndrome/acute myeloid leukemia, and survival in patients with aplastic anemia (AA) surviving more than 1 year after ATG/ALG-based immunosuppressive therapy (IST) between 1985 and 2020. Four-hundred seventy patients (413 adults and 57 children) were studied, and data were compared with 223 patients who underwent matched sibling donor transplant (MSD HSCT). Median follow-up is 50 months (12-359). Relapse occurred in 21.9% at a median time of 33.5 months (5-228) post IST. Twenty-six (5.5%) patients progressed to PNH, while 20 (4.3%) evolved to MDS/AML. Ten-year estimated overall survival (OS) is 80.9 ± 3% and was significantly better in patients without an event (85.1 ± 4%) compared to relapse (74.6% ± 6.2%) or clonal evolution (12.8% ± 11.8%) (p = 0.024). While the severity of AA (p = 0.011) and type of ATG (p = 0.028) used predicted relapse, only age at IST administration influenced clonal evolution (p = 0.018). Among HSCT recipients, relapse rates were 4.9% with no clonal evolution, and the 10-year OS was 94.5 ± 2%. In patients who survived 1 year following IST, outcomes were good except with clonal evolution to MDS/AML. These outcomes, however, were still inferior compared to matched sibling donor HSCT.

Treatment challenges and outcomes of older patients with acute myeloid leukemia from India.

Globally, overall survival (OS) of older patients with AML continues to be suboptimal with very little data from India. In a multicenter registry analysis, we evaluated 712 patients with AML older than 55 years. Only 323 (45.3%) underwent further treatment, of which 239 (74%) received HMAs, and 60 (18%) received intensive chemotherapy (IC). CR was documented in 39% of those receiving IC and 42% after HMAs. Overall, 100 (31%) patients died within 60 days of diagnosis, most commonly due to progressive disease (47%) or infections (30%). After a median follow-up of 176 days, 228 (76%) of patients had discontinued treatment. At one year from diagnosis, 211 (65%) patients had died, and the median OS was 186 days (IQR, 137-234). Only 12 (3.7%) patients underwent stem cell transplantation. Survival was significantly lower for those older than 60 years (p < 0.001). Patients who died had a higher median age (p = .027) and baseline WBC counts (p = .006). Our data highlights suboptimal outcomes in older AML patients, which are evident from 55 years of age onwards, making it necessary to evaluate HMA and targeted agent combinations along with novel consolidation strategies to improve survival in this high-risk population.

Total marrow lymphoid irradiation and cyclophosphamide is associated with low toxicity and good outcomes in patients undergoing hematopoietic stem cell transplantation for acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crises - A phase I study.

INTRODUCTION: Total marrow lymphoid irradiation (TMLI) can deliver higher doses of irradiation without increasing toxicity compared to Total body irradiation (TBI). METHODS: Twenty adult patients undergoing hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia with lymphoid blast crises (CML-LBC) received TMLI and cyclophosphamide for conditioning. Ten patients each received 13.5 or 15 Gy of TMLI. The graft source was peripheral blood stem cells in all, and donors included matched related (n = 15), haplo-identical (n = 3) or matched unrelated donors (n = 2). RESULTS: The median cell dose infused was 9 × 106 CD34/kg (range 4.8-12.4). Engraftment occurred in all (100%) at a median of 15 days (range: 14-17). Toxicity was low with hemorrhagic cystitis seen in two but no sinusoidal obstruction syndrome. Acute GVHD occurred in 40% while chronic GVHD was seen in 70.5%. Viral infections were seen in 55% while blood stream bacterial infections occurred in 20% and invasive fungal disease (IFD) in 10%. The Day 100 non-relapse mortality (NRM) was 10%. At a median follow up of 25 months (range 2-48), two patients have relapsed. Overall survival at 2 years is 80% while the disease-free survival is 75%. CONCLUSIONS: The combination of TMLI and cyclophosphamide for myeloablative conditioning is associated with low toxicity and favorable early outcomes in patients undergoing HSCT for ALL and CML-LBC.

Molecular characterization of triple-negative myeloproliferative neoplasms by next-generation sequencing.

The role of next-generation sequencing (NGS) in identifying mutations in the driver, epigenetic regulator, RNA splicing, and signaling pathway genes in myeloproliferative neoplasms (MPNs) has contributed substantially to our understanding of the disease pathogenesis as well as disease evolution. NGS aids in determining the clonal nature of the disease in a subset of these disorders where mutations in the driver genes are not detected. There is a paucity of real-world data on the utility of this test in the characterization of triple-negative myeloproliferative neoplasms (TN-MPN). In this study, 46 samples of TN-MPN (essential thrombocythemia (ET) = 17; primary myelofibrosis (PMF) = 23; & myeloproliferative neoplasm unclassified (MPN-u) = 6) were screened for markers of clonality using targeted NGS. Among these, 25 (54.3%) patients had mutations that would help determine the clonal nature of the disease. Eight of the 17 TN-ET (47%) and 13 of the 23 TN-PMF (56.5%) patients had noncanonical mutations in the driver genes and mutations in the genes involved in epigenetic regulation. Identification of mutations categorized as high molecular markers (HMR) in 2 patients helped classify them as PMF with high risk according to the MIPSS 70 scoring system. A novel mutation in the MPIG6B (C6orf25) gene associated with childhood myelofibrosis was detected in a 14-year-old girl. The presence of clonal hematopoiesis could be confirmed in four of the six MPN-u patients in this cohort. This study demonstrates the utility of NGS in improving the characterization of TN-MPN by establishing clonality and detecting noncanonical mutations in driver genes, thereby aiding in clinical decision-making.

Improving Outcomes with Haploidentical Stem Cell Transplantation [HaploSCT] in Children Using Post-transplant Cyclophosphamide: a Single Center Experience.

Haplo-identical stem cell transplant using post-transplant cyclophosphamide is increasingly being used in children without a matched sibling donor. Between 2010 and June 2021, 127 children underwent 138 transplants with a median age of 7.1 years for malignant and non-malignant disorders. Conditioning regimens included both myeloablative and reduced intensity regimens with peripheral blood stem cells as the main graft source. Engraftment occurred in 113 [81.9%] at a median of 16 days [range: 10-32] with primary graft failure in 10.2%. Cumulative incidence of grade II-IV acute graft versus host disease (GVHD) was 49.5% and chronic GVHD in 40.7%. Majority [92.7%] had at least one infection with 31% incidence of bacterial infection, 76% incidence of viral and 16% incidence of fungal infection. The 2-year overall survival (OS) is 54.9 ± 4.6% with a lower survival among young children aged 0-5 years [28.2 ± 6.4%] compared to 5-10 years [71.3 ± 6.8%] and 11-15 years [55.7 ± 8.8%] [p = 0.032]. 2-year OS has gradually improved from 25.0 ± 2.1% for 2010-2013 to 47.5 ± 6.2% for 2014-2017 and 67.1 ± 6.6% for 2018-2021 [p = 0.049]. On multivariate analysis, bacterial infection [p = 0.017], invasive fungal disease [p = 0.002] and graft failure [p = 0.029] negatively impacted overall survival. Haplo-identical SCT with post-transplant cyclophosphamide is a reasonable option for children who do not have a matched sibling donor. Strategies to reduce graft failure, infection related mortality and GVHD needs to be explored.

Biomarkers of coagulation, endothelial, platelet function, and fibrinolysis in patients with COVID-19: a prospective study.

Prospective and sequential evaluation of homeostatic changes leading to thrombosis across COVID 19 disease severity spectrum are limited. In this prospective observational study, haemostasis was evaluated in patients with mild, moderate-severe, and critical COVID-19 infection. Markers of endothelial activation [Soluble thrombomodulin (sTM), von Willebrand Factor (VWF)], platelet activation [Soluble P-selectin, beta-thromboglobulin (BTG)] and global haemostasis [Rotational thromboelastometry (ROTEM)] were evaluated on days 1 and 5 after admission. The study cohort comprised of 100 adult patients (mild = 20, moderate-severe = 22, critical = 58). Sixty-five patients received anticoagulation for 10 (7-14) days. Thrombotic events were seen in 9 patients. In-hospital mortality was 21%. Endothelial activation markers were elevated at baseline in all subgroups, with levels in moderate-severe (sTM = 4.92 ng/ml, VWF = 295 U/dl) [reference-ranges: sTM = 2.26-4.55 ng/ml; Soluble P-selectin = 13.5-31.5 ng/ml; BTG = 0.034-1.99 ng/ml] and critical patients (sTM = 6.07 ng/ml, VWF = 294 U/dl) being significantly higher than in the mild group (sTM = 4.18 ng/ml, VWF = 206 U/dl). In contrast, platelet activation markers were elevated only in critically ill patients at baseline (Soluble P-selectin = 37.3 ng/ml, BTG = 2.51 ng/ml). The critical group had significantly lower fibrinolysis on days 1 and 5 when compared with the moderate-severe arm. COVID-19 infection was associated with graded endothelial activation and lower fibrinolysis that correlated with illness severity.

Profile and Predictors of Infection Following Anti-thymocyte Globulin or Anti-lymphocyte Globulin with Cyclosporine in Aplastic Anemia.

Immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and Cyclosporine (CSA) in aplastic anaemia (AA) results in improvement of blood counts between 3 and 6 months for the majority of patients. Infection is the most lethal complication in aplastic anemia and may arise due to several factors. We performed this study to determine the prevalence and predictors of specific infection types before and after IST. Six hundred and seventy-seven (546 adults; 434 males) transplant ineligible patients received ATG and CSA between 1995 and 2017. All patients who were transplant ineligible and received IST in this period were included. Infections before IST was seen in 209 (30.9%) and in 430 (63.5%) patients post IST. There were 700 infective episodes in the six months post-IST, including 216 bacterial, 78 fungal, 33 viral, and 373 culture-negative febrile episodes. Infections were highest (98, 77.8%) in very severe aplastic anaemia as compared to Severe AA (SAA) and Non-Severe AA (NSAA) (p < 0.001). Infections were also significantly higher in those who did not respond to ATG (71.1% vs. 56.8%, p = 0.003). At six months post-IST were 545 (80.5%) alive, and there were 54 (7.9%) deaths due to infection. Significant predictors of mortality were paediatric AA, very severe aplastic anaemia, pre or post ATG infections, and lack of response to ATG. Mortality was highest in those with combined bacterial and fungal infections post IST (p < 0.001). We conclude that infections are a common complication (63.5%) of IST. Mortality was highest when both bacterial and fungal infections were present. Routine use of growth factors and prophylactic antifungal and antibacterial agents was not part of our protocol, despite which 80.5% of the cohort was alive at the end of six months.

Decentralized manufacturing of anti CD19 CAR-T cells using CliniMACS Prodigy®: real-world experience and cost analysis in India.

Chimeric Antigen Receptor (CAR) T cell therapy is an accepted standard of care for relapsed/refractory B cell malignancies. However, the high cost of existing industry-driven centralized production makes this therapy unaffordable in low and middle-income countries. Decentralized or point of care manufacturing has the potential to overcome some of these challenges. Here we demonstrate a decentralized manufacturing process for anti-CD19-CAR-T cells using a fully automated closed system (Miltenyi CliniMACS Prodigy®) is feasible in a developing country setting. Validation run data, as part of a pre-clinical trial safety evaluation, demonstrates the successful and robust manufacturing of anti-CD19 CAR-T cells with T cell expansion of 25 to 47-fold. The median transduction efficiency was 48.8%, with a median viability of 98% and fulfillment of all standard release criteria assays for clinical application. Evaluation of production costs in an academic, not for profit setting in India provide a benchmark for low and middle-income pricing which could greatly increase access to this therapy. Based on our analysis, the cost per product would be approximately $35,107 US dollars. Our data highlights the safety, efficacy, and reproducibility of the process for use in planned future clinical trials.

Haploidentical Natural Killer Cell Therapy as an Adjunct to Stem Cell Transplantation for Treatment of Refractory Acute Myeloid Leukemia.

Refractory acute myeloid leukemia (AML), defined as failure of two cycles of induction therapy at diagnosis or of one cycle at relapse, represents a subgroup with poor outcomes. Haploidentical natural killer cell (NK) therapy is a strategy that is being explored in refractory malignancies. Historically, at our center, patients with refractory AML have been treated with cytoreductive therapy (fludarabine + cytosine + granulocyte colony-stimulating factor ± idarubicin or mitoxantrone + etoposide) followed by 1-week rest and then reduced-intensity transplant with fludarabine + melphalan. We used the same backbone for this trial (CTRI/2019/02/017505) with the addition of CD56-positive cells from a family donor infused 1 day after the completion of chemotherapy. CD56-positive selection was done using a CliniMACS Prodigy system (Miltenyi Biotec, Bergisch Gladbach, Germany) followed by overnight incubation in autologous plasma with 2 micromolar arsenic trioxide and 500 U/mL of interleukin-2. From February 2019, 14 patients with a median age of 29 years (interquartile range [IQR]: 16.5-38.5) were enrolled in this trial. Six were females. Six had primary refractory AML while eight had relapsed refractory AML. The median CD56-cell dose infused was 46.16 × 106/kg (IQR: 25.06-70.36). One patient withdrew consent after NK cell infusion. Of the 13 patients who proceeded to transplant, five died of immediate post-transplant complications while two did not engraft but were in morphologic leukemia-free state (both subsequently died of infective complications after the second transplant). Of the remaining six patients who engrafted and survived beyond 1 month of the transplant, two developed disease relapse and died. The remaining four patients are alive and relapse free at the last follow-up (mean follow-up duration of surviving patients is 24 months). The 2-year estimated overall survival for the cohort was 28.6% ± 12.1% while the treatment-related mortality (TRM) with this approach was 38.5% ± 13.5%. Haploidentical NK cell therapy as an adjunct to transplant is safe and needs further exploration in patients with AML. For refractory AML, post-transplant NK infusion and strategies to reduce TRM while using pre-transplant NK infusion merit exploration.

Clinical significance of end of induction measurable residual disease monitoring in B-cell acute lymphoblastic leukemia: A single center experience.

The assessment of measurable residual disease (MRD) has emerged as a powerful prognostic tool for both pediatric and adult acute lymphoblastic leukemia (ALL). This retrospective study aimed to evaluate the prognostic relevance of the end of induction MRD in B-cell acute lymphoblastic leukemia (B ALL) patients. The study included 481 patients who underwent treatment for B ALL between August 2012 and March 2019 and had their MRD at the end of induction assessed by flow cytometry. Baseline demographic characteristics were collected from the patient's clinical records. Event free survival (EFS) and relapse free survival (RFS) were calculated using Kaplan-Meier analysis and survival estimates were compared using the log-rank test. End of induction MRD and baseline karyotype were the strongest predictors of EFS and RFS on multivariate analysis. The EFS was inversely related to the MRD value and the outcomes were similar in patients without morphological remission at the end of induction and patients in remission with MRD ≥1.0%. Even within the subgroups of ALL based on age, karyotype, BCR::ABL1 translocation and the treatment protocol, end of induction MRD positive patients had poor outcomes compared to patients who were MRD negative. The study outcome would help draft end of induction MRD-based treatment guidelines for the management of B ALL patients.

Fludarabine-Based Low-Intensity Conditioning for Fanconi Anemia is Associated with Good Outcomes in Aplastic Anemia but not in MDS - a Single-Center Experience.

Background: Hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with Fanconi Anemia (FA) with hematological abnormalities. Materials and Methods: This is a retrospective analysis of patients with FA who underwent a matched-related donor HSCT. Results: Sixty patients underwent 65 transplants between 1999-2021 using a fludarabine-based low-intensity conditioning regimen. The median age at transplant was 11 years (range: 3-37). Aplastic anemia (AA) was the underlying diagnosis in 55 (84.6%), while 8 (12.4%) had myelodysplastic syndrome (MDS) and 2 (3%) had acute myeloid leukemia (AML). The conditioning regimen used was Fludarabine with low-dose Cyclophosphamide for aplastic anemia and Fludarabine with low-dose Busulfan for MDS/AML. Graft versus host disease (GVHD) prophylaxis consisted of Cyclosporine and methotrexate. Peripheral blood was the predominant stem cell graft source (86.2%). Engraftment occurred in all but one patient. The median time to neutrophil and platelet engraftment was 13 days (range: 9-29) & 13 days (range: 5-31), respectively. Day 28 chimerism analysis showed complete chimerism in 75.4 % and mixed chimerism in 18.5%. Secondary graft failure was encountered in 7.7%. Grade II-IV acute GVHD occurred in 29.2%, while Grade III-IV acute GVHD occurred in 9.2%. Chronic GVHD was seen in 58.5% and was limited in most patients. The median follow-up is 55 months (range: 2-144) & the 5-year estimated overall survival (OS) is 80.2 ± 5.1%. Secondary malignancies were noted in 4 patients. The 5-year OS was significantly higher in patients undergoing HSCT for AA (86.6 + 4.7%) as compared to MDS/AML (45.7+16.6%) (p= 0.001). Conclusion: SCT using a fully matched donor provides good outcomes with low-intensity conditioning regimens in patients with FA who have aplastic marrow.

Hematopoietic Stem Cell Transplantation is a cost-effective alternative to enzyme replacement therapy in Gaucher Disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a feasible treatment option for Gaucher disease (GD). Among 60 patients diagnosed with GD over 15 years (2004-2019), three children who underwent HSCT (January-November 2017) were analyzed. Two boys (cases 1 and 2) and one girl (case 3) received HSCT at 3, 7, and 10 years of age, respectively. Cases 1 and 3 received haplo-HSCT, while case 2 received HLA-identical related-donor transplantation. The CD 34 cell dose was 5-10×106/kg. Neutrophil and platelet engraftment were between days +14 to +21 and days +15 to +76. Post-HSCT chimerism was a 100% donor. None of the patients developed acute or significant chronic graft versus host disease (GVHD). All patients had febrile episodes with negative blood cultures. Major post-HSCT complications included EBV-viremia and recurrent lobar pneumonia in case 1, delayed engraftment and pure red cell aplasia (PRCA) in case 2, and pericardial effusion with tamponade in case 3. At a median of 49 months post-HSCT, all patients were stable with improved growth, absent organomegaly, and had completed immunization. The median cost of treatment was $23,038.96, which is 10.7%-13% of the yearly enzyme replacement therapy (ERT) cost. In a resource-limited setting like India, ERT is a financial burden and not a sustainable option. With improved treatment outcomes, haplo-HSCT is now a possible option for almost every patient, even if no HLA-identical donor is identified.

Single Dose of Ivermectin is not Useful in Patients with Hematological Disorders and COVID-19 Illness: A Phase II B Open Labelled Randomized Controlled Trial.

Repurposed drugs may reduce morbidity and mortality in patients with hematological disorders who develop COVID-19 illness. 112 patients with predominantly hematological illnesses were randomized to receive standard of care, ivermectin 12 mg [Iv 12] or 24 mg [Iv24] for asymptomatic, mild, or moderate COVID 19 illness. Serial respiratory samples for rRT-PCR samples were sent on Day 3, 5 and 7. rRT-PCR negativity and ≥ 2 log10 reduction in viral loads on day 3, 5 and 7 were similar between the 3 treatment groups across all disease categories. Symptom progression occurred in 26 patients [21.6%] with no difference across 3 treatment groups. Twenty-two patients [18.3%] have expired while 98 [81.7%] survived. Survival rates were similar across treatment groups [controls-80.5%, Iv12-77.5%, Iv24-87.2% respectively]. Overall, poorer survival was seen with moderate illness compared to others [51.6% vs 92.1%; p = 0.000] and was the only significant risk factor identified on multivariate analysis. In this Phase II randomised trial, single dose of 12 or 24 mg of ivermectin did not reduce viral loads, prevent symptom progression, or reduce mortality in patients with predominantly haematological illnesses who develop mild to moderate COVID 19 illness.

Endothelial Activation and Stress Index-Measured Pretransplantation Predicts Transplantation-Related Mortality in Patients with Thalassemia Major Undergoing Transplantation with Thiotepa, Treosulfan, and Fludarabine Conditioning.

The use of thiotepa-treosulfan-fludarabine conditioning regimen and peripheral blood stem cell grafts is associated with improved outcomes of hematopoietic stem cell transplantation (HCT) in patients with high-risk thalassemia major. However, there remains a need to identify predictors of poor outcomes in this cohort to further optimize outcomes. The Endothelial Activation and Stress Index (EASIX) is a biomarker shown to predict survival in various settings, including graft-versus-host disease, veno-occlusive disease, and nonrelapse mortality following allogeneic HCT. In this retrospective analysis, we evaluated the role of EASIX-PreTx (measured before conditioning therapy) as a biomarker in predicting day +100 transplantation-related mortality (TRM+100) in 281 patients with thalassemia major who underwent HCT with a uniform conditioning regimen using thiotepa-treosulfan-fludarabine at our center between January 2012 and December 2019. The median patient age was 9 years (range, 1 to 25 years), and 109 (38.8%) were females. According to the Pesaro classification (with Vellore modification), 3 patients (1.1%) were class I, 34 (12.1%) were class II, 134 (47.7%) were class III low risk, and 110 (39.1%) were class III high risk. Stem cell donors were matched sibling (n = 218; 77.6%), matched related nonsibling (n = 23; 8.2%), or matched unrelated (n = 40; 14.2%). Five patients (1.8%) received a bone marrow graft, and the others received a peripheral blood stem cell graft. Thirty-eight patients (13.5%) had TRM+100. EASIX-PreTx was available for 184 patients (65.5%). The median EASIX-PreTx was significantly higher in patients with TRM+100 compared with those without TRM+100 (1.09 versus .75; P = .008). An EASIX-PreTx cutoff of .85 had 70.4% sensitivity and 62% specificity for predicting TRM+100. The TRM+100 for patients with EASIX-PreTx >.85 was significantly higher than those with EASIX <.85 (24.4% versus 7.5%; P = .003). In a uniform subgroup of class III patients undergoing allogeneic HCT (n = 156), EASIX-PreTx was an independent predictor of TRM+100.

Haploidentical transplantation is feasible and associated with reasonable outcomes despite major infective complications-A single center experience from India.

Haploidentical stem cell transplantation (SCT) using post-transplantation cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis is a reasonable therapeutic option for patients who do not have a matched sibling donor. Between 2010 and June 2020, 257 patients underwent 269 Haploidentical transplantations, including 122 children. Indications included both malignant (56.8%) and non-malignant (43.2%) diseases. Conditioning regimens included both myeloablative (57.6%) and nonmyeloablative regimens (42.4%). Peripheral blood stem cells were the predominant graft source (96.2%). Based on the disease risk index, patients were classified into early-, intermediate-, and late-stage disease. Engraftment was seen in 205 patients (76.2%) whereas 39 (14.4%) died before engraftment and 23 (8.6%) had primary graft failure. The cumulative incidence of grade II-IV acute GVHD was 47.8% with a 23.9% incidence of grade III-IV acute GVHD. Chronic GVHD was seen in 41.9% with a 15.4% incidence of extensive chronic GVHD. More than 90% had at least 1 documented infection with a 44% incidence of bacterial, 71% viral, and 38% fungal infection. The 2-year overall survival is 40.5% ± 3.2% with a higher survival among children (48.2% ± 3.4%) compared to adults (34.2% ± 4.1%). Survival was poor with late-stage disease (23.6% ± 4.3%) compared to early- (62.5% ± 7.5%) and intermediate-stage (50.3% ± 4.3%). Factors adversely affecting survival included older age of patient (P = .007), late disease status (P = .000), nonmyeloablative conditioning regimen (P = .003), bone marrow as graft source (P = .006), presence of acute GVHD (P = .069), primary graft failure (P = .000), and presence of a documented bacterial (P = .000) and fungal infection (P = .000). On multivariate analysis, older age (P = .027), presence of acute GVHD (P = .033), documented bacterial infection (P = .000), documented fungal infection (P = .000) and primary graft failure (P = .012) continued to remain significant. Haploidentical SCT offers a reasonable chance of cure for patients with both malignant and nonmalignant hematological diseases. Strategies to reduce aGVHD and infection related mortality needs to be explored further. © 20XX American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

An Antithymocyte Globulin-Free Conditioning Regimen Using Fludarabine and Cyclophosphamide Is Associated with Good Outcomes in Patients Undergoing Matched Related Family Donor Transplantation for Aplastic Anemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) using fludarabine (Flu)-based conditioning regimens are being increasingly being used in patients with aplastic anemia (AA). We describe an antithymocyte globulin (ATG)-free conditioning regimen consisting of Flu and cyclophosphamide (Cy) in patients undergoing matched related donor (MRD) HSCT for AA. Between 2004 and 2019, 212 patients underwent MRD HSCT using Flu (30 mg/m2/day for 6 days) and Cy (60 mg/kg/day for 2 days) for conditioning. The graft source was peripheral blood stem cells in all patients. Graft-versus-host disease (GVHD) prophylaxis consisted mainly of cyclosporine and methotrexate, although 41 patients received post-transplantation Cy as part of a study. Engraftment occurred in 91% of patients at a median of 16 days, whereas 4 patients (1.8%) experienced primary graft failure and 15 (7.1%) died before achieving engraftment. Toxicity was minimal. The incidence of grade II-IV acute GVHD (aGVHD) was 27.9%, and that of grade III-IV aGVHD was 11.3%. Chronic GVHD occurred in 41.6%. 80% were free of immunosuppression at 60 months and long-term complications were seen in 8.4%. At a median of 46 months, 158 patients were alive and well, with a 5-year overall survival (OS) of 75.3 ± 3.0%. The 5-year OS was 80.6 ± 4.1% for patients age <20 years (n = 93), 74.5 ± 4.6% for those age 20 to 40 years (n = 91), and 59.7 ± 9.5% for those age >40 years (n = 28) (P = .11). Patients classified as low risk had better OS compared with those at high risk (93.2 ± 2.9% versus 65.7 ± 4.1%; P = .000). Factors affecting OS on multivariate analysis included aGVHD (P = .02) and graft failure (P = .000). This large series using Flu/Cy for conditioning before MRD HSCT confirms good outcomes in patients with AA, with excellent outcomes in low-risk patients. Suitable modifications are needed to improve outcomes in high-risk patients.