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Introduction: Pneumocystis jirovecii pneumonia (PJP) is a rare complication of hematopoietic stem cell transplantation (HSCT). Primary prophylaxis for 6–12 months post‐HSCT is the standard approach. However, there is no consensus regarding the optimal duration of prophylaxis. Methods: We identified patients who developed PJP more than 1‐year post‐HSCT. All patients had previously received 12 months of PJP prophylaxis. PJP was diagnosed based on clinical findings and the detection of P. jirovecii in bronchoalveolar lavage (BAL) using polymerase chain reaction (PCR). The CD4+ T‐cell percentage was determined using flow cytometry. Data expressed as median (interquartile range). Results: Ten patients developed PJP at 17.5 months (16–24 months) post‐HSCT. PJP diagnosis occurred 5.5 months (3–15 months) after discontinuing prophylaxis. Eight patients received anti‐thymocyte globulin (ATG) as graft versus host disease (GVHD) prophylaxis. At diagnosis, only one patient had lymphopenia; all patients had CD4+ T‐lymphocyte counts ≥0.2 × 109/L (median 0.337 × 109/L). Three patients had concomitant bacterial infections. The clinical presentation was mild; only three required hospitalization, none of them required intensive care and there were no deaths. Conclusion: There is a need to develop risk‐adapted prophylactic strategies in the contemporary era using ATG‐based GVHD prophylaxis. [ABSTRACT FROM AUTHOR]

Summary: Emerging biological and clinical data, along with advances in new technologies, have exposed the mechanistic diversity in post‐haematopoietic stem cell transplant (HCT) relapse. Post‐HCT relapse mechanisms are relevant for guiding sophisticated selection of therapeutic interventions and identification of areas for further research. Clonal evolution and emergence of resistant leukemic strains is a common mechanism shared by relapse post‐chemotherapy and post‐HCT, other mechanisms such as leukemic immune escape and donor T cell exhaustion are unique entities to post‐HCT relapse. Due to diversity in the mechanisms behind post‐HCT relapse, the subsequent clinical approach relies on clinician discretion, rather than objective evidence. Lack of standardized selection based on post‐HCT relapse mechanism(s) could be a contributing factor to observed poor outcomes. Therapeutic strategies including donor lymphocyte infusion (DLI), second transplant, immunotherapies, hypomethylating agents, and targeted strategies are supported options and efficacy may be enhanced when post‐HCT AML relapse mechanism is established and guides treatment selection. This review aims, through compilation of supporting studies, to describe mechanisms of post‐HCT relapse and their implications for subsequent treatment selection and inspiration for future research. [ABSTRACT FROM AUTHOR]

Summary: Multiple studies have reported a significant treatment‐free remission (TFR) rate of 50%–60% in patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitor (TKI) therapy. However, the remaining half of these patients still require re‐initiation of TKI therapy for leukaemia control. It remains unclear if TKI drugs should be switched for re‐therapy in patients who failed the first TFR (TFR1) attempt. Our study attempted to determine whether dasatinib therapy after TFR1 failure post‐imatinib discontinuation could improve the likelihood of TFR2. Of 59 patients who lost molecular response after imatinib discontinuation for TFR1, 55 patients (93.2%) were treated with dasatinib, of whom 49 (89.1%) regained MR4.5 or deeper response, with a median time of 1.85 months to achieve MR4.5. Dasatinib was discontinued in 35 patients for TFR2 attempt, of whom 26 patients (74.28%) lost MMR and 6 (17.14%) MR4. Risk factor analysis for the TFR2 after dasatinib discontinuation suggested three significant factors: (1) doubling time of BCR::ABL1 transcript following TFR1 attempt, (2) rapid regaining of molecular response following dasatinib therapy and (3) undetectable BCR::ABL1 transcript prior to TFR2 attempt. The present study showed that dasatinib does not increase the TFR2 rate in general, but a selected group of patients could benefit from this approach. [ABSTRACT FROM AUTHOR]

Summary: The doubling time (DT) of the BCR–ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re‐growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT was calculated as x = ln(2)/K, where x is the DT and K is the fold BCR–ABL1 change from the previous value divided by the number of days between each measurement. The optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high‐risk group (DT<12·75 days but >0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse‐free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate‐risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low‐risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P < 0·001). Monthly assessment of DT helps identify high‐risk patients for treatment‐free remission failure with an imminent risk of molecular recurrence, and to define low‐risk patients who can be spared the frequent monitoring of monthly molecular tests. [ABSTRACT FROM AUTHOR]

Objectives: Hepatic grading systems for categorizing severity in chronic graft‐versus‐host disease (cGvHD) were determined arbitrarily, leading us to initiate the present study to provide objective evidence for the determination of optimal cutoff values and devise a hepatic grading system to predict prognosis. Methods: Of 842 patients who received allogeneic hematopoietic stem transplant (HCT), 336 patients diagnosed with cGvHD were evaluated for overall survival (OS) and non‐relapse mortality (NRM) after cGVHD development. Multiple statistical parameters were evaluated to define optimal cutoff values of liver profile, including negative predictive value (NPV), positive predictive value (PPV), accuracy, and p‐values as measures of risk stratification power. Results: We found that alkaline phosphatase (ALP) ≥ 146 IU/L (NPV: 83.4%; PPV: 32.8%; accuracy: 52.7%) and bilirubin ≥ 14 µmol/L (NPV: 81.8%; PPV: 39.4%; accuracy 68.1%) significantly correlated with OS. We developed a refined hepatic cGvHD grading score (RHS), stratifying patients into a low‐RHS group with RHS score 0, OS at 3 years (n = 162) to 80.5%, compared to high‐RHS group with score 1‐2 (n = 172) 62.7%. Regarding NRM, score 0 segregated NRM at 3 years to 11.9%, compared with score 1‐2 19.6%, P =.1. Conclusions: Refined hepatic score is promising for stratifying patients with cGVHD and liver involvement according to long‐term outcomes. [ABSTRACT FROM AUTHOR]

Introduction: The polypeptide prolactin (PRL) is a peptide hormone and a cytokine mostly secreted from the anterior pituitary gland. PRL is also synthesized in extra pituitary tissues including thymocytes and T lymphocytes. Considering the need for chronic GVHD (cGVHD) biomarkers, we explored the relationship between hyperprolactinemia and active cGVHD in a cohort of long‐term post‐alloHCT survivors. Methods: Three‐hundred sixteen adults underwent alloHCT between 2010 and 2016, survived more than 1 year and were included. All patients underwent a regular annual assessment that includes a hormone profile with serum PRL levels. Results: Overall, 236 (74.7%) patients had cGVHD, and in 199 (63%), the grade was moderate or severe. Sixty‐five (21%) recipients had active cGVHD at the time of the annual evaluation, and hyperprolactinemia was documented in 63 (19.9%) patients. Hyperprolactinemia correlated with cGVHD activity (Odds Ratio 6.9 (95% CI; 3.6‐13.1); P <.001) in the multivariate analysis. In conclusion, patients with hyperprolactinemia were 6.4 times more likely to have active cGVHD in comparison with those patients with normal levels of PRL (P <.001). Conclusion: Prolactin may serve as a biomarker for cGVHD activity. Further studies are required to confirm these findings, and to explore if hyperprolactinemia has an impact on cGVHD severity and prognosis. [ABSTRACT FROM AUTHOR]

Introduction: Recent advances in allogeneic hematopoietic stem cell transplant (HSCT) have allowed us to offer HSCT to older, advanced disease patients with more co‐morbidities. Cardiovascular toxicity post‐transplant is a major concern due to the increased risk of mortality. Few studies have examined the prevalence of CV events including CAD (MI, angina, PCI, CABG, CHF, arrhythmias), HTN, stroke/TIA, and death in the first 100 days post‐transplant. Patients: We assessed the impact of pretransplant MUGA results in predicting postallogeneic HSCT CV events and overall survival in the first 100 days, and whether or not transient anthracycline‐induced cardiomyopathy or cumulative anthracycline dose affected overall survival. This retrospective, cohort study included 665 patients with a median age of 52 years who underwent HSCT from 2009 to 2015. Results: The most frequent CV event in the first 100 days post‐HSCT was arrhythmia seen in 2.9% of patients followed up by CHF (12.3%), MI (9%), and angina (8%). Two patients had PCI, and both survived the first 100 days. Cardiovascular risk factors predict for a poor MUGA scan but not survival. Higher dose anthracycline pretransplant predicted for a poor outcome. Conclusion: A history of CV disease, MI, or CAD was the most important predictive of CV events, P‐value =.00002. 88.6% survived the first 100 days. Patients with an EF < 50% had a significant likelihood of having a CV event compared to patients with an EF > 60% (OR = 5.3, 95% CI [1.6‐18.1], P =.0219). Cumulative anthracycline dose did not have a significant impact on overall survival. [ABSTRACT FROM AUTHOR]

Introduction: Therapy‐related acute lymphoblastic leukemia (t‐ALL) is an increasingly recognized subset of therapy‐related acute leukemia. There are limited data on the role of allogeneic hematopoietic stem cell transplantation (HSCT) in t‐ALL. Recent reports suggest comparable outcomes of t‐ALL with de novo ALL after HSCT. Patients and Methods: We retrospectively reviewed all patients of t‐ALL who underwent HSCT at our center. Patients were analyzed for prior malignancy, therapy, time to diagnosis of t‐ALL, clinical, laboratory characteristics, transplant details, relapse‐free survival (RFS), and overall survival (OS). Results: Eighteen patients (M:F ratio 1:1; Median age 44 years) underwent HSCT for t‐ALL. Median latent period from primary malignancy to t‐ALL was 44.8 months. 11q23 rearrangement and t(9;22) were present in 33.3% and 22.2% patients, respectively. Stem cell donors were matched related, matched unrelated, and haploidentical in 27.8% (n = 5), 55.6% (n = 10), and 16.7% (n = 3) patients, respectively. Five patients died before D+ 100 (27.8%). Estimated 2‐year RFS and OS were 47.1% and 51.8%, respectively. We did not find any pretransplant and post‐transplant risk factors that were predictive of improved OS or RFS after multivariate analysis. Conclusions: Allogeneic HSCT outcomes in t‐ALL were comparable to HSCT outcomes in de novo ALL. Multicenter studies with more patients and longer follow‐up may provide factors affecting outcome and survival. [ABSTRACT FROM AUTHOR]

Objectives: Haploidentical hematopoietic stem cell transplant (haplo‐SCT) has been associated with higher rates of graft rejection, and a higher dose of CD34+ cell dose is frequently requested. We aim to explore the impact of CD34+ cell dose in peripheral blood stem cell (PBSC) grafts using reduced intensity conditioning (RIC) in haplo‐SCT. Methods: Sixty‐eight consecutive haplo‐SCT in adult patients were included. Graft‐vs‐host disease (GVHD) prophylaxis consisted on ATG, PTCy, and CsA. The cohort was divided in two groups using CD34+ dose of ≥ 9 × 106 CD34+/Kg as cutoff point. Median follow‐up was 8.9 months. Results: Median cell dose infused was 9.32 × 106 CD34+/Kg. Forty (58.8%) recipients received grafts with CD34+ cells ≥9 × 106/kg. The infusion ≥ 9 × 106 CD34+/Kg cell dose had a negative impact in overall survival (P =.03) after adjusting for age at transplant. The cumulative incidence of acute GVHD and graft failure were not significantly influenced per CD34+ cell dose. Only four recipients had grade III aGVHD, and all of them received grafts with a CD34+ cell dose ≥ 9 × 106. Conclusion: In RIC haplo‐SCT, recipients may not benefit from PBSC grafts with a CD34+/kg cell dose higher than 9 × 106 cells/kg, as it can have an adverse impact in post‐transplant outcome. [ABSTRACT FROM AUTHOR]

Background: There remains a significant mortality in recipients with MF who undergo allogeneic stem cell transplant (allo‐HSCT). The combination of antithymocyte globulin (ATG) and post‐transplant cyclophosphamide (PTCy) provides good control of graft‐versus‐host disease (GVHD) when peripheral blood stem cell grafts are used. Methods: We report the outcome of 37 recipients with myelofibrosis who underwent reduced‐intensity conditioning (RIC) allo‐HSCT with ATG and PTCy. Median follow‐up was 16.4 months. Results: Nine (24.3%) recipients received 10/10 MRD grafts, 17 (45.9%) 10/10 MUD grafts, 4 (10.8%) 9/10 MUD grafts, and 7 (18.9%) haploidentical donor grafts. Six (16.3%) patients had graft failure. The cumulative incidence of grade II‐IV and grade III‐IV aGVHD at day +100 and moderate/severe chronic GVHD at 1 year was as follows: 13.5%, 5.4%, and 17%. There were no deaths secondary to GVHD. One‐year overall survival (OS), relapse‐free survival (RFS), non‐relapse mortality (NRM), and GVHD‐free/RFS (GRFS) were respectively 74.4%, 71.3%, 23%, and 43.3%. Those recipients who had worse KPS ≤ 80% had worse OS and RFS. Conclusion: RIC allo‐HSCT with ATG and PTCy results in high OS and RFS in patients with myelofibrosis and absence of mortality secondary to GVHD. Further investigations are required to reduce NRM and graft failure rates. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to study the efficacy of reduced intensity conditioning (RIC) allo‐HSCT combined with anti‐thymocyte globulin (ATG) and post‐transplant cyclophosphamide (PTCy) for graft‐versus‐host disease (GVHD) prophylaxis in AML. Methods: One hundred forty‐seven patients were included. All patients underwent unmanipulated peripheral blood stem cell RIC allo‐HSCT. Median follow‐up was 12.8 months (range 0.5‐39). Results: Median age was 58 years. Twenty‐nine (20%) recipients received 10/10 MRD grafts, 69 (47%) 10/10 MUD grafts, 20 (13.6%) 9/10 MMUD, and 29 (20%) haploidentical grafts. The cumulative incidence of grade II‐IV and III‐IV acute GVHD at day +100, and moderate/severe chronic GVHD at 1‐year were as follow: 14.3%, 1.4%, and 8.3%. There were no significant differences according to donor type (P = .46) and cumulative incidence of GVHD. One‐year overall survival (OS), relapse‐free survival (RFS), non‐relapse mortality, and GVHD‐free/Relapse‐free survival were as follows: 66.9% (95% CI 58.4‐74), 59.9%, and 18.7% and 53.7%. KPS ≤ 80 was predictive of worst OS (P = .04). Those recipients who received MUD transplants had better RFS (P = .01). Conclusions: RIC allo‐HSCT combined with ATG and PTCy is safe and a potentially curative strategy and it is associated with impressive GRFS in AML. [ABSTRACT FROM AUTHOR]

Objective: The primary objective was to assess the effect of central nervous system involvement in acute myeloid leukemia (CNS‐AML) on outcomes after allogeneic hematopoietic stem cell transplant (allo‐HCT). The secondary objective was to assess the utility of pretransplant cerebrospinal fluid (CSF) assessment in AML. Methods: We retrospectively analyzed survival outcomes in 338 adult AML patients (with and without CNS‐AML) after allo‐HCT. CNS involvement was defined as clinical, pathological, or radiological evidence of CNS involvement any time after diagnosis. Results: The median follow‐up in surviving patients was 23.7 months. Twenty‐five patients (7.4%) had prior history of CNS disease, with normal CSF pretransplant. Three patients had CSF blasts detected for the first time at pretransplant evaluation (0.88%). The 2‐year OS and RFS in groups with and without CNS involvement were not significantly different. Patients with CNS‐AML had significantly higher 1‐year cumulative incidence of relapse (29.7% vs 16.9%, P = .048). Age more than 65 years and absence of marrow remission at transplant were significant adverse factors for survival. Conclusion: CNS‐AML is not an independent risk factor for survival after allo‐HCT, but can be associated with higher relapse rates. Pretransplant CSF assessment has low yield in detecting new CNS disease pretransplant in AML. [ABSTRACT FROM AUTHOR]

Introduction: We evaluated the combination of ATG and PTCy for GVHD prophylaxis in matched and mismatched unrelated PBSCTs for high‐risk hematological malignancies. Methods: We treated 102 patients with reduced intensity conditioning (RIC) with fludarabine, busulfan, and TBI 200 cGy. GVHD prophylaxis included rabbit ATG (thymoglobulin at total dose of 4.5 mg/kg divided over days −3 to −1), PTCy (50 mg/kg/day on day +3 and on day +4), and cyclosporine. Clinical and outcome data were collected retrospectively. Results: Among 102 patients, 76 patients received 10/10 MUD transplants and 26 patients received 9/10 mismatched transplants. The median age was 59 years. At a median follow‐up of 15 months (range 0.6 to −33 months), the 1‐year OS in MUD and MMUD cohort was 75% and 50%, respectively (P = 0.027). The corresponding one‐year PFS was 67% and 35%, respectively (P = 0.0024). The incidence of grade 3‐4 acute GVHD was 11.8% in MUD and 3.8% in MMUD group, and that of NIH stage moderate/severe chronic GVHD in the 2 groups was 10.5% and 7.6%, respectively. Cytomegalovirus (CMV) reactivation was seen in 49% patients. The cumulative incidence of relapse was 21.1% in the MUD group and 42.3% in the MMUD group. Conclusion: Our experience shows that PTCy and ATG can be combined for GVHD prophylaxis in matched unrelated donor PBSCTs with low rates of Gr3‐4 acute GVHD and chronic GVHD, and acceptable relapse rates. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Second allogeneic hematopoietic cell transplantation (HCT) may be indicated following relapse or graft failure following first HCT. Our retrospective single‐center study sought to investigate parameters that influence post‐second allogeneic HCT survival. Method: We investigated 92 patients who underwent second allogeneic HCT between 1980 and 2016 for relapse or graft failure following first HCT. Median age at second HCT was 41 years (range 16‐68), performed for relapse in 59 patients (64%) and for graft failure in 33 patients (36%). Results: On univariate analysis, 3‐year OS of the entire cohort was 35% (95% CI=25‐45). Eastern Cooperative Oncology Group (ECOG) score (3‐year OS 48% for ECOG 0‐1, 18% for ECOG 2‐3, P=.0006), second HCT indication (3‐year OS 43% for relapse, 20% for graft failure, P=.02), time from first HCT to relapse/graft failure (3‐year OS for <12months 21%, for ≥12months 46%, P=.009), and conditioning intensity (3‐year OS for MA 42% vs other regimens 23%, P=.08) significantly influenced OS. Multivariable analysis confirmed ECOG score (HR=2.15 for ECOG 2‐3, 95% CI=1.32‐3.51, P=.002) and second HCT indication (HR=1.67 for graft failure, 95% CI=1.02‐2.75, P=.04) to independently influence survival. Conclusion: Second HCT may offer long‐term survival particularly to patients with good performance status who relapse post‐first HCT. [ABSTRACT FROM AUTHOR]

An increase in large granular lymphocytes ( LGL) is frequently seen in patients following allogeneic hematopoietic cell transplantation (allo- HCT) and it has been associated with better outcomes in some reports. We assessed 826 consecutive patients at our institution with over 12 years of follow-up for the occurrence of LGL lymphocytosis after allo- HCT. The 3-year cumulative incidence of LGL lymphocytosis was 14.5% with a median duration of over 3.5 years. The development of LGL lymphocytosis was strongly correlated with CMV viremia and GVHD. The clinical course of patients with LGL lymphocytosis after allo- HCT was indolent, with the majority of these patients not displaying any clinical signs or symptoms related to the LGL proliferation. LGL lymphocytosis was associated with better outcomes, including higher overall survival ( OS 86.6% vs 44.7% at 3 years), lower non-relapse mortality ( NRM 5.5% vs 30.4% at 3 years), and lower risk of relapse (8.9% vs 22.9% at 3 years). A time-dependent multivariable analysis confirmed the favorable impact of LGL lymphocytosis on OS and NRM, but not on the risk of relapse. In multivariable analysis, a longer duration of LGL lymphocytosis was associated with better OS and NRM. Improved immunomodulatory properties of these cells, regulating GVHD and infections, may explain the observed favorable outcomes of patients who developed LGL lymphocytosis following allo- HCT. [ABSTRACT FROM AUTHOR]