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In the elderly population, the accelerated and blastic phases of chronic myeloid leukemia (CML) are difficult to treat, not just because of the higher chance of acquired mutations than in younger individuals, but because of additional associated co-morbidities. Tyrosine kinase inhibitors are well-established in the treatment of the chronic phase of CML, and their use in advanced phases is ever-increasing. Elderly patients who are still eligible candidates for transplant can undergo reduced-intensity transplants from related or unrelated donors after reverting to chronic phase. Post-transplantation, these patients require adequate monitoring and therapy to prevent relapses. Newer modalities of treatment or interventions are urgently required in this complex group of patients.

Background: We aimed to develop multiple single-nucleotide polymorphism (SNP)-based risk models associated with the risk of transplant outcomes including graft-versus-host disease (GVHD)., Methods: The study evaluated 259 SNPs in 53 genes in 394 pairs of donors and recipients. In a discovery set (n=307 receiving related donor transplantation), overall survival, relapse-free survival (RFS), nonrelapse mortality, and acute or chronic GVHD were evaluated., Results: Eight recipients' SNPs of IL2, IL6R, FAS, EDN1, TGFB1, and NFKBIA genes and 12 donors' SNPs of NOS1, IL1B, TGFB2, NOD2/CARD15, TNFRII, IL1R1, and FCGR2A genes were identified in univariate analyses. Risk models were generated using significant clinical variables and genetic SNP markers after filtering out through multivariate analyses. Then, we divided patients into four quartiles (25%, Q) according to their risks. The final models stratified patients into low-risk (Q1), moderate-risk (Q2, Q3), and high-risk (Q4) groups in terms of overall survival (P<0.0001), RFS (P<0.0001), nonrelapse mortality (P=0.0043), and acute GVHD (P<0.0001), but not for chronic GVHD (P=0.763). External validation was performed in 87 transplant pairs that received matched unrelated donor transplantation, especially for RFS (P=0.016) and acute GVHD (P=0.027)., Conclusion: Risk models can improve prognostic stratification of patients according to their risk for transplant outcome.

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]

Allogeneic hematopoietic stem cell transplantation (HCT) is associated with significant morbidity and mortality. Elevated pre-transplant ferritin level (ferritinPre-HCT) is reported to be associated with increased mortality following HCT. The present study attempted to determine whether post-transplant ferritin level (ferritinPost-HCT) is associated with outcomes post-HCT, especially in the subgroups which developed acute or chronic graft-versus-host disease (GVHD). Out of 229 patients with serum ferritin level measured post-HCT, median ferritinPost-HCT was 2178 ng/mL. Patients were stratified into low- or high-risk groups using recursive partitioning, based on ferritinPost-HCT (≤ 3169 vs > 3169 ng/mL) and ferritinPre-HCT (≤ 669 vs > 669 ng/mL). Compared to the low ferritinPost-HCT group, the high ferritinPost-HCT group had lower 3-year overall survival (OS) (40.0% vs 66.7%, p < 0.001) and higher non-relapse mortality (NRM) (48.6% vs 17.8%, p < 0.001), but no difference in relapse (10.5% vs 19.7%, p = 0.079). Multivariate analysis confirmed ferritinPost-HCT as an independent prognostic factor for OS (p = 0.001, HR = 2.323) and NRM (p < 0.001, HR = 3.905). However, ferritinPre-HCT did not stratify well for OS or NRM. FerritinPost-HCT was also found to be an independent prognostic marker for OS and NRM in the subgroups which developed GVHD. In our cohort, high ferritinPost-HCT levels were significantly associated with decreased OS and increased NRM independent of ferritinPre-HCT or GVHD. Additional studies including larger sample sizes and prospective investigation are warranted to clarify the prognostic significance and pathophysiology of pre- and post-transplant hyperferritinemia. [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]

The present study attempted to build a single nucleotide polymorphism (SNP)-based risk model for predicting overall survival (OS) and event-free survival (EFS) in patients with core binding factor acute myeloid leukemia (CBF-AML). Adopting genome-wide SNP array using Affymetrix SNP array 6.0, we analyzed 868,157 SNPs with respect to OS and EFS in 104 patients with CBF-AML. Significant SNPs were identified from single SNP analysis. The risk model was constructed with incorporation of six SNPs and three clinical factors (age, c-kit exon 17 mutation, and LDH) for OS and six SNPs and three clinical factors (age, WBC, and LDH) for EFS. The model was further defined into low- and high-risk groups based on risk scores. The median age was 39 years, and the subgroup of t(8;21) and inv(16) or t(16;16) was assessed in 68 (65.4%) and 36 patients (34.6%). Finally, six SNPs per each OS (rs4353685, rs4908185, rs7709207, rs12034, rs1554844, and rs17241868) and EFS (rs13385610, rs11210617, rs11169282, rs7709207, rs4438401, and rs16894846) were incorporated into the risk model. OS was significantly different in favor of the low risk group (80.4 ± 8.4%) compared to the high-risk group (22.0 ± 7.3% at 3 years; p = 8.75 × 10- 13; HR 8.67). For EFS, there was also a significant difference between the low- (75.0 ± 5.8%) versus high-risk group (17.1 ± 6.3% at 3 years; p = 5.95 × 10- 13; HR 7.67). A genome-wide SNP-based risk model can stratify CBF-AML patients according to their OS and EFS in 104 patients. [ABSTRACT FROM AUTHOR]

The CIBMTR chronic graft-versus-host disease (cGVHD) risk score can be refined and improved for better prognostic stratification. Three hundred and seven consecutive patients diagnosed with cGVHD by the NIH consensus criteria were retrospectively reviewed and had the CIBMTR risk score applied and analyzed. The CIBMTR risk score was successfully validated in our cohort (n = 307). The 3-year overall survival (OS) rates in each risk group (RG) were 82.5 ± 11.3% (RG1), 79.4 ± 3.0% (RG2), 71.8 ± 6.3% (RG3), and 27.3 ± 13.4% (RG4). A significantly lower OS rate and higher non-relapse mortality (NRM) were noted in RG4 compared to the other RGs. However, there were no differences in OS or NRM among RG1 to 3. To improve prognostic stratification power of the CIBMTR risk score, we incorporated the absolute lymphocyte (ALC) and eosinophil count (EC) at time of cGVHD into the CIBMTR risk score. Lower ALC (<1.0 × 109/L, HR 1.94, p = 0.014) and lower EC (<0.5 × 109/L, HR 3.27, p = 0.014) were confirmed as adverse risk factors for OS. Patients were stratified into four revised risk groups (rRG). The 3-year OS rates were 93.3 ± 6.4% (rRG1, score 0-3), 84.9 ± 3.4% (rRG2, score 4-6), 70.9 ± 4.4% (rRG3, score 7-9), and 32.0 ± 1.1% (rRG4, score ≥ 10) (p < 0.001). The 3-year NRM rates were 0.0% (rRG1), 6.7 ± 0.4% (rRG2), 18.4 ± 0.7% (rRG3), and 57.7 ± 5.1% (rRG4) (p < 0.001). The revised CIBMTR risk score was superior to the original CIBMTR risk score for OS (p < 0.001). The revised CIBMTR risk score including ALC and EC at the onset of cGVHD improved the prognostic stratification power of the CIBMTR risk score for long-term outcomes. [ABSTRACT FROM AUTHOR]

The article presents the study that investigates the effectiveness of allogeneic hematopoietic stem cell transplantation in the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in Canada. The topics discussed include the symptoms associated with the BPDCN, the results of the randomized controlled trial that evaluates the efficacy of acute lymphoblastic leukemia (ALL) in treating BPDCN, and the patients overall survival.

Highlights • A 1.3 log reduction in BCR-ABL levels within 3 months post HCT is prognostic in TKI resistance or intolerance. • HCT remains a potential cure for patients with CML resistant or intolerant of TKI therapy. • Advanced phase disease remains a poor prognostic factor post HCT even in the TKI era. Abstract The majority of patients with TKI failure respond to HCT. However, the relapse risk remains high. This study has evaluated transplant outcomes in 223 CML patients with TKI failure due to resistance (n = 132) or intolerance (n = 29), as well as those that were TKI naïve/responding with advanced disease (n = 35) or with chronic phase (CP, n = 27). We studied outcomes according to post-transplant BCR-ABL transcript level within 3 months. With respect to transplant outcomes according to the post-transplant BCR/ ABLtranscript level within 3 months, the group failing to achieve a 1.3 log reduction (n = 14, 12.4%) showed the highest relapse rate of 78.6% at 5 years, compared to 26.2% and 24.1% in the groups achieving 1.3–4.0 log reduction (n = 45, 39.8%), and ≥4.1 log reduction (n = 54, 47.8%) respectively (p < 0.001). Multivariate analysis confirmed that the group failing to achieve a 1.3 log reduction had a 2.3-fold higher risk of death and 6.6 times higher risk of relapse. Poor overall survival after HCT was associated with advanced disease at diagnosis, but not disease status prior to HCT. Of 61 patients who relapsed after HCT, 47 were treated with post-transplant TKI therapy; those receiving TKI after loss of MR2 or MMR showed higher rates of response and survival compared to those receiving TKI after hematologic relapse (p < 0.001). QPCR log reduction level within 3 months post transplantation is prognostic in this population. [ABSTRACT FROM AUTHOR]