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Background: Selection of CD34+ PBPCs has been applied as a method of reducing graft contamination from neoplastic cells. This procedure seems to delay lymphocyte recovery, while myeloid engraftment is no different from that with unselected PBPC transplants.Study Design and Methods: Lymphocyte recovery was studied in two groups of patients who underwent autologous CD34+ PBPC transplant with two different technologies (Ceprate SC, Cellpro [n = 17]; CliniMACS, Miltenyi Biotech [n = 13]). The median number of CD34+ cells transfused was 3.88 x 10(6) per kg and 3.32 x 10(6) per kg, respectively. Residual CD3 cells x 10(6) per kg were 4.97 and 0.58, respectively (p = 0.041). Residual CD19 cells x 10(6) per kg were 1.33 and 0.73, respectively (NS).Results: No differences were found between the two groups in total lymphocyte recovery to >0.5 x 10(9) per L, which achieved a stable count by Day 30. During the study period, the CD4+ cell count remained below 0.2 x 10(9) per L, and the B-cell subset showed a trend toward normalization. CD3/HLA-DR+ and CD16/56 increased markedly in both groups by Day 30. An increase in CMV (13%) and adenovirus (17.4%) infection was found in both groups.Conclusion: Both CD34+ cell selection technologies used here determined an excellent CD34+ cell purity and an optimal depletion of T cells. The high rate of viral complications is probably due to the inability of residual T cells left from the CD34+ cell selection to generate, immediately after transplant, an adequate number of virus-specific lymphocytes. [ABSTRACT FROM AUTHOR]

Highly fluorescent reticulocyte (HFR) counts are the most reliable and sensitive index of haemopoietic recovery after bone marrow or peripheral blood stem cell transplantation. We report the behaviour of HFRs during haemopoietic recovery in two patients who were affected by severe aplastic anaemia (SAA) and treated with horse antithymocyte globulin (ATG), cyclosporin A (CsA) and granulocyte colony-stimulating factor (G-CSF). A HFR value > 5% of the total reticulocyte count, a reticulocyte count > 30 × 109/l, and a polymorphonuclear (PMN) count > 0.5 × 109/l were found after 9 and 8, 20 and 46, and 16 and 22 days, respectively, after the end of ATG. HFR recovery to > 5% anticipated the rise of PMN > 0.5 × 109/l by at least 7 and 14 days, respectively. Thus, HFR evaluation could be used as a reliable and early marker of response to immunosuppression in severe aplastic anaemia. [ABSTRACT FROM AUTHOR]

Factor V Leiden is one of the most common genetic conditions predisposing to venous thrombosis. Diagnosis is currently made by plasma activity assay for activated protein C (APC) resistance or polymerase chain reaction (PCR)-based DNA assay. The occurrence of factor V Leiden is reported in a patient affected by acute myeloid leukaemia submitted to allogeneic bone marrow transplantation from an HLA identical sister. The donor was not affected by the factor V mutation. The patient did not develop thrombosis during induction and consolidation chemotherapy and the post-transplantation course was not complicated by thrombosis or veno-occlusive disease. At engraftment, PCR analysis showed the disappearance of factor V Leiden. Genetic tests on DNA after allogeneic marrow transplantation should be carefully interpreted as a result of donor chimerism. [ABSTRACT FROM AUTHOR]

CD4 + and CD8 + chimeric antigen receptor T cells (CAR-T) play different roles in the in vivo anti-tumour response, but the role of the CD4 + /CD8 + ratio among infused CAR-T has not been clearly defined yet. We analysed leftovers from infused anti-CD19 CAR-T bags of 31 patients with aggressive B-cell lymphomas. The median ratio was 1.44, lower for brexu-cel compared to tisa-cel and axi-cel. The CAR+CD4 + /CD8 + ratio was influenced by lactate dehydrogenase levels at apheresis, not by age, previous treatments or the CD4 + /CD8 + ratio in peripheral blood. Patients with a response at 3 months after CAR-T (M3) had a lower CAR+CD4 + /CD8 + ratio in the infused products compared to non-responders (ratio 0.74 vs. 2.47, p = 0.011). A CAR+CD4 + /CD8 + ratio higher than the cut point of 1.12 was associated with an increased risk of treatment failure at M3 (OR 23.3, p = 0.012) and M6 (OR 10, p = 0.028). The median 6-month PFS was 76% for patients with a ratio lower than 1.12% vs. 31% for the others. The prognostic role of the CAR+CD4 + /CD8 + ratio was independent of the costimulatory domain (CD28 vs. 4-1BB) of the product (OR 16.41, p = 0.041). Our data indicate a crucial role for CD8 + CAR-T and the CAR+CD4 + /CD8 + ratio in predicting CAR-T efficacy., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Cytokine release syndrome (CRS) and consumptive coagulopathy can complicate the treatment with chimeric antigen receptor T (CAR-T) cells. The modified version of the Endothelial Activation and Stress Index (mEASIX), a score derived from haematopoietic stem cell transplantation, combines platelets, C-reactive protein (CRP), and lactate dehydrogenase (LDH) and has been correlated with CRS and endothelial biomarkers. In 38 consecutive patients with aggressive lymphoproliferative disease we measured a coagulative laboratory panel at baseline and early after infusion of anti-CD19 CAR-T. The panel was investigated also in the presence of CRS graded 2 or higher, or immune effector cell-associated neurotoxicity syndrome (ICANS). Moreover, we examined the relationship between mEASIX, coagulation biomarkers, and toxicities of CAR-T cells. During CRS grade 2 or higher, we found increased prothrombin time (PT) and activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, factor VIII (FVIII), and von Willebrand factor (vWF) antigen levels, and decreased platelet count and antithrombin levels. The occurrence of immune effector cell-associated neurotoxicity syndrome was associated with higher PT values, D-dimer, FVIII, and vWF levels, and decreased fibrinogen levels and platelet count. A higher mEASIX score correlated with increased aPTT values, fibrinogen, D-dimer, FVIII and vWF levels, and decreased antithrombin levels. Baseline mEASIX was predictive for consumptive coagulopathy and CRS graded 2 or higher, and for progression-free survival and overall survival., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The best stem cell source for T-cell replete human leukocyte antigen (HLA)-haploidentical transplantation with post-transplant cyclophosphamide (PTCy) remains to be determined. In this European Society for Blood and Marrow Transplantation retrospective study, we analyzed the impact of stem cell source on leukemia-free survival (LFS) in adult patients with primary refractory or relapsed acute myeloid leukemia (AML) given grafts from HLA-haploidentical donors with PTCy as graft-versus-host disease (GVHD) prophylaxis. A total of 668 patients (249 bone marrow [BM] and 419 peripheral blood stem cells [PBSC] recipients) met the inclusion criteria. The use of PBSC was associated with a higher incidence of grade II-IV (HR = 1.59, p = .029) and grade III-IV (HR = 2.08, p = .013) acute GVHD. There was a statistical interaction between patient age and the impact of stem cell source for LFS (p < .01). In multivariate Cox models, among patients <55 years, the use of PBSC versus BM resulted in comparable LFS (HR = 0.82, p = .2). In contrast, in patients ≥55 years of age, the use of PBSC versus BM was associated with higher non-relapse mortality (NRM) (HR = 1.7, p = .01), lower LFS (HR = 1.37, p = .026) and lower overall survival (HR = 1.33, p = .044). In conclusions, our data suggest that in patients ≥55 years of age with active AML at HLA-haploidentical transplantation, the use of BM instead of PBSC as stem cell source results in lower NRM and better LFS. In contrast among younger patients, the use of PBSC results in at least a comparable LFS., (© 2022 Wiley Periodicals LLC.)

The aim of this retrospective study was to assess the rate of full donor chimerism (F-DC) in patients with myelofibrosis, prepared for an allogeneic stem cell transplant, with one or two alkylating agents. We analyzed 120 patients with myelofibrosis, for whom chimerism data were available on day +30. There were two groups: 42 patients were conditioned with one alkylating agent (ONE-ALK), either thiotepa or busulfan or melphalan, in combination with fludarabine, whereas 78 patients were prepared with two alkylating agents, thiotepa busulfan and fludarabine (TBF). Patients receiving TBF were older (57 vs 52 years), were less frequently splenectomized pre-HSCT (31% vs 59%), had more frequently intermediate-2/high DIPSS scores (90% vs 74%), were grafted more frequently from alternative donors (83% vs 33%) and received more frequently ruxolitinib pre-HSCT (26% vs 7%). The proportion of patients with F-DC on day +30, in the TBF vs the ONE-ALK group, was respectively 87% vs 45% (P < .001). The 5-year cumulative incidence of relapse was 9% in the TBF group, vs 43% for the ONE-ALK group (P < .001). The 5-year actuarial disease-free survival was 63% for TBF and 38% for the ONE-ALK group (P = .004). In conclusion, early full donor chimerism is a prerequisite for long term control of disease in patients with myelofibrosis, undergoing an allogeneic HSCT. The combination of two alkylating agents in the conditioning regimen, provides a higher chance of achieving full donor chimerism on day+30, and thus a higher chance of long term disease free survival., (© 2020 Wiley Periodicals LLC.)

The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI) vs chemotherapy (CT) based MAC regimens in acute myeloid leukemia (AML) patients. The study included 1008 patients who underwent first haplo-HCT with post-transplant cyclophosphamide, following TBI (N = 89, 9%) or CT (n = 919, 91%) based MAC. Patients in the TBI cohort were younger (median age, 38 vs 47 years, P < .01) and more likely to receive BM graft (57% vs 43%, P = .01). Two-year overall chronic GVHD (cGVHD) incidence was 42% vs 27% (P < .01) and extensive cGVHD incidence was 9% vs 12% (P = .33) in TBI and CT cohorts, respectively. Graft failure was reported in two (2%) TBI- and 65 (7%) CT-MAC recipients (P = .08). Death from veno-occlusive disease was reported in one (3%) TBI and 11 (3%) CT patients who died during the study period. In the multivariate analysis, TBI was associated with increased risk for overall cGVHD (hazard ratio = 1.95, 95% confidence interval:1.2-3.1, P < .01) compared to CT-based MAC. The choice of conditioning regimen did not impact relapse incidence, leukemia-free survival, non-relapse mortality, overall survival or GVHD-relapse-free survival in multivariate analysis. In conclusion, major transplant outcomes were not statistically different between TBI-based MAC and CT-based MAC in patients with AML after haplo-HCT/PTCy., (© 2020 Wiley Periodicals LLC.)

A low count of CD4 + and CD8 + lymphocytes is a hallmark laboratory finding in the coronavirus disease 2019 (COVID-19). Using flow cytometry, we observed significantly higher CD95 (Fas) and PD-1 expression on both CD4 + T and CD8 + T cells in 42 COVID-19 patients when compared to controls. Higher CD95 expression in CD4 + cells correlated with lower CD4 + counts. A higher expression of CD95 in CD4 + and CD8 + lymphocytes correlated with a lower percentage of naive events. Our results might suggest a shift to antigen-activated T cells, expressing molecules increasing their propensity to apoptosis and exhaustion during COVID-19 infection., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

POEMS syndrome is a rare paraneoplastic condition, with a poorly understood pathogenesis. High dose chemotherapy followed by autologous stem cell transplantation (ASCT) has been reported to be an effective therapeutic option for patients with good performance status. Here, we review the role of ASCT for POEMS syndrome and discuss indications together with advantages and disadvantages, and related issues such lenalidomide given before or after ASCT, VEGF levels as a marker of disease, and different regimens for stem cell mobilization., (Copyright © 2017 John Wiley & Sons, Ltd.)

A disease risk index (DRI) has been defined for stratifying heterogeneous cohorts of patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT). This index defines 4 distinct groups with different outcomes, dividing patients by disease type and status and considering cytogenetics for acute myeloid leukaemia and myelodysplastic syndromes (MDS). Recently, the DRI has been refined to include rare diseases and improve MDS stratification by blast percentage and response to prior therapy. Previous reports on DRI include only a small number of UCBT recipients. The current study aims to determine the applicability of the DRI for patients undergoing unrelated cord blood transplantation (UCBT). We retrospectively analysed 2530 adults receiving UCBT between 2004 and 2014. Diagnosis was acute leukaemia (AL) in 66% of the cases. Overall survival (OS) at 2 years was 56 ± 3% for patients with low DRI (n = 352), 46 ± 1% for intermediate DRI (n = 1403), 28 ± 2% for high (n = 489) and 20 ± 4% for very high DRI (n = 109) (P < 0·001). In the multivariate model, DRI remained an independent risk factor for OS. Similar findings were observed for PFS and DRI. Our results show the applicability of DRI for stratifying UCBT recipients and confirm the prognostic value of this simple and robust tool in this setting., (© 2017 John Wiley & Sons Ltd.)

The most frequent BCR-ABL1 fusion transcripts in chronic myeloid leukemia (CML) are the e13a2 (b2a2) and the e14a2 (b3a2) ones. In the imatinib era few studies addressing the prognostic significance of the BCR-ABL1 transcript type in early chronic phase CML have been published. Overall, these studies suggest that in e14a2 patients the response to imatinib is faster and deeper. To evaluate if the BCR-ABL1 transcript type (e13a2 compared to e14a2) affect the response to imatinib and the clinical outcome in newly diagnosed adult CML patients, 559 patients enrolled in 3 prospective studies (NCT00514488, NCT00510926, observational study CML/023) were analyzed. A qualitative PCR was performed at baseline: 52% patients had a e14a2 transcript, 37% a e13a2 transcript, 11% co-expressed both transcripts and 1% had other rare transcripts. The median follow-up was 76 months (95% of the patients had at least a 5-year observation). The complete cytogenetic response rates were comparable in e14a2 and e13a2 patients. The median time to MR 3.0 (6 and 12 months) and MR 4.0 (41 and 61 months) was significantly shorter for e14a2 patients compared to e13a2 patients, with a higher cumulative probability of MR 3.0 (88% and 83%, P < .001) and MR 4.0 (67% and 52%, P = .001). The 7-year overall survival (90% and 83%, P = .017), progression-free survival (89% and 81%, P = .005) and failure-free survival (71% and 54%, P < .001) were significantly better in patients with e14a2 transcript. In conclusion, patients with e13a2 transcript had a slower molecular response with inferior response rates to imatinib and a poorer long-term outcome., (© 2017 Wiley Periodicals, Inc.)

The aim of this study was to identify risk factors for mortality in patients suffering from hematological malignancies (HMs) with bloodstream infections (BSIs) caused by Klebsiella pneumoniae (KP). We conducted a prospective cohort study on KP BSI in 13 Italian hematological units participating in the HEMABIS registry-SEIFEM group. The outcome measured was death within 21 days of BSI onset. Survivor and non-survivor subgroups were compared and Cox regression analysis was conducted to identify independent predictors of mortality. A total of 278 episodes of KP BSI were included in the study between January 2010 and June 2014. We found that 161 (57.9%) KP isolates were carbapenem resistant (CRKP). The overall 21-day mortality rate was 36.3%. It was significantly higher for patients with CRKP BSI (84/161, 52.2%) than for those with BSI caused by carbapenem susceptible KP (CSKP) (17/117, 14.5%; P < 0.001). Septic shock (HR 3.86), acute respiratory failure (HR 2.32), inadequate initial antimicrobial therapy (HR 1.87) and carbapenem resistance by KP isolates (HR 1.85) were independently associated with mortality. A subanalysis was conducted in only 149 patients with CRKP BSI who had received ≥48 hr of adequate antibiotic therapy, and combination therapy was independently associated with survival (HR 0.32). Our study shows that in recent years carbapenem resistance has dramatically increased in HM patients with KP BSI in Italy and is associated with a worse outcome. The optimal management of such infections and the definition of new empirical/targeted antimicrobial strategies in HM patients can still be considered unmet clinical needs. Am. J. Hematol. 91:1076-1081, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Therapy-related myeloid neoplasms (t-MN) are a complication of cytotoxic treatment for primary tumors and autoimmune diseases. We report data on 277 t-MN patients, recruited between 1999 and 2013 by the Italian Network on Secondary Leukemias (104 retrospectively and 173 prospectively registered). Median age at t-MN diagnosis was 64 years (range, 21-87). Most frequent primary malignancies (PMs) were lymphoproliferative diseases and breast cancer. One hundred and thirty-three patients had received chemotherapy (CHT), 43 patients radiotherapy (RT), and 101 patients combined CHT/RT for PM. Median time between cytotoxic treatment and t-MN was 5.7 years, with t-MN following RT alone associated with significantly longer latency, compared to CHT or combined CHT/RT (mean, 11.2 vs. 7.1 years, P = 0.0005). The addition of topoisomerase-II inhibitors to alkylating agents was associated with shorter latency compared to alkylating agents alone (median, 6 vs. 8.4 years, P = 0.02). Median survival was 14.6 months from t-MN diagnosis, and was significantly longer in patients treated with allogeneic stem cell transplantation. Significant factors for survival at the multivariable analysis included age, adverse karyotype, and degree of anemia. Our data underline the prognostic importance of karyotype and age in t-MN, similar to de novo acute myeloid leukemia. Treatment approaches should not preclude the use of conventional treatments for younger t-MN patients, including allogeneic stem cell transplantation as potentially curative approach., (© 2015 Wiley Periodicals, Inc.)

We investigated the role of stem cell purification and G-CSF (early vs. delayed vs. no G-CSF) administration on hemopoietic recovery and supportive care requirements after stem cell transplantation. Thirty-two patients submitted to autologous CD34(+) peripheral blood stem cell transplantation (PBSCT) were studied, and data were compared to patients undergoing unfractionated peripheral blood stem cell transplantation (uPBSCT) matched for age, disease, and conditioning regimen. Except for PMN, hemopoietic recovery was significantly slower and supportive care requirements were significantly higher after CD34(+) PBSCT. Median time to PMN >0.5 x 10(9)/l was 13 days (range 9-27) and 13 d (range 9-23); reticulocytes (Ret) >1% was 14.5 d (range 12-34) and 12 d (range 10-27); high-fluorescence reticulocytes (HFR) >5% was 12 d (range 9-26) and 9 d (range 7-11); platelets >50 x 10(9)/l and >100 x 10(9)/l was 20 d (range 10-240), 12 d (range 9-60) and 33 d (range 15-720), 15 d (range 11-210). When the analysis was performed on subgroups of patients (early/delayed/no G-CSF), early G-CSF significantly promoted PMN recovery (>0.5 x 10(9)/l and >1.0 x 10(9)/l) compared to no G-CSF, without affecting RBCs or platelet recovery. Delayed G-CSF did not improve PMN recovery compared to patients not receiving G-CSF, did not result in a significant reduction of drug requirements, and had a negative impact on erythroid and platelet recovery. In conclusion, these preliminary data suggest that G-CSF is useful if given early after CD34(+) PBSCT. CD34(+) PBSCT may overall require a significant increase of resource utilization that should be outweighed by proven clinical benefit., (Copyright 2002 Wiley-Liss, Inc.)

The recovery of lymphocyte count, CD4+ and CD8+ T-cell subsets, natural killer (NK) cells and CD19+ B-cells was evaluated in a cohort of 15 patients receiving autologous CD34+ peripheral blood progenitor cells (PBPCs; group A) for haematological malignancies and in 20 patients transplanted with autologous unselected PBPCs (group B). Lymphocyte count recovered in both patient cohorts, being significantly lower in group A than in group B 1 (P = 0.008) and 2 months (P = 0.0035) after progenitor cell infusion. The repopulation of CD3+ T-cells occurred more rapidly in group B than in group A (P = 0.034 on week 4); CD19+ B-lymphocytes did not return to reference ranges in either group of patients. The count of CD4+ T-lymphocytes remained < 200/microl during the study period in patients transplanted with CD34+ PBPCs, significantly lower than group B levels (P = 0.034 and P = 0.021 on weeks 4 and 8 respectively). CD8+ T-cells increased rapidly in both groups; thus, the CD4 to CD8 ratio was severely reduced. CD4+ and CD8+ T-cells displayed an activated phenotype in both groups of patients, co-expressing the HLA-DR antigen throughout the study period. NK cells followed a similar repopulation kinetics in both study groups, although their expansion was greater in group B than in group A (P = 0.014 on week 4). In the CD34+ group, post-transplant administration of granulocyte colony-stimulating factor predicted a faster lymphocyte recovery in multivariate analysis (P = 0.025); interestingly, the amount of passively transferred lymphocytes correlated inversely with time to achieve a lymphocyte count > 0.5 x 10(9)/l (r = -0.63, P = 0.01). Further investigations are necessary to characterize T-cell competence after transplantation of CD34+ PBPCs.