Comparison of Different Rabbit Anti-Thymocyte Globulin Formulations in the Prophylaxis of Graft-Versus-Host Disease: A Systematic Review.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment modality, frequently used for patients suffering from haematological malignancies. In the last two decades, there have been multiple randomised controlled trials (RCTs), review articles, and meta-analyses addressing the efficacy of rabbit anti-thymocyte globulin (r-ATG) as a graft-versus-host disease (GvHD) prophylaxis. Nevertheless, only a few aimed to compare the effectiveness of different r-ATG formulations. Since the last article we retrieved comparing different r-ATGs in GvHD prophylaxis dates back to 2017, we performed a systematic literature review of articles published since 2017 to this day, utilising PubMed, Scopus, Cochrane, and MEDLINE, with the main endpoints being prophylaxis of acute GvHD (aGvHD) and chronic GvHD (cGvHD). We subjected to scrutiny a total of five studies, of which four compared the differences between Thymoglobulin (ATG-T) and Grafalon (ATG-G), and one discussed the impact of ATG-T dose. Overall, cGvHD, aGvHD grades II-IV, TRM, OS, NRM, LFS, relapse, overall infections, and EBV reactivation do not seem to be affected by the type of utilised rATG. However, data on aGvHD grades III-IV, GRFS, moderate-severe cGvHD, and CMV reactivation is conflicting. Through our research, we sought to summarise the most recent findings concerning r-ATGs in allo-HCT, and provide insight into the differences between the targets and origin of various ATG formulations.

Therapeutic adherence and assessment of satisfaction patients with multiple myeloma treated with immunomodulatory drugs in a "real-world" study: Experiences of the Polish Myeloma Group.

INTRODUCTION: Therapeutic adherence (TA) is one of the most important factors influencing the effectiveness of treatment. Oral anti-cancer drugs are increasingly used to treat malignancy including multiple myeloma (MM). Our study aimed to determine TA of patients with MM treated with IMiDs, to identify TA risk factors, and to determine satisfaction with medical care during the treatment with IMiDs. METHODS: A cross-sectional survey-based study involving adult patients with MM treated with IMiDs. RESULTS: Between January 2021 and May 2021, 267 patients with MM were enrolled in the study. The dosing schedule was declared as easy by 71.8% of patients, as standard for 24.0%, and difficult for 4.2% of patients. During MM treatment, 85.0% of patients did not skip any IMiDs dose, and 87.6% did not skip the IMiDs dose in the last cycle of chemotherapy. Identified factors affecting TA included the treatment duration and education level. In addition, depending on the patient's well-being, gender, and household companionship influenced TA. Satisfaction with medical care during the treatment with IMiDs was declared by 95.5% of patients with MM. In our cohort, 95.5% of patients were satisfied with the information they received from the hematologist during treatment with IMiDs. CONCLUSIONS: Patients with MM treated with IMiDs are highly adherent to treatment. With time from the beginning of treatment, patients need more attention and motivation to adhere to the therapy rules.

Ofatumumab with iphosphamide, etoposide and cytarabine for patients with transplantation-ineligible relapsed and refractory diffuse large B-cell lymphoma.

The efficacy of salvage treatment of diffuse large B-cell lymphoma (DLBCL) patients who relapse or progress (rrDLBCL) after initial therapy is limited. Efficacy and safety of ofatumumab with iphosphamide, etoposide and cytarabine (O-IVAC) was evaluated in a single-arm study. Dosing was modified for elderly patients. Patients received up to six cycles of treatment. The primary end-point was the overall response rate (ORR). Patients were evaluated every two cycles and then six and 12 months after treatment. Other end-points included progression-free survival (PFS), event-free survival (EFS), overall survival (OS) and safety. Seventy-seven patients received salvage treatment with O-IVAC. The average age was 56.8 years; 39% had an Eastern Cooperative Oncology Group (ECOG) performance status of at least 3; 78% had disease of Ann Arbor stage 3 or 4; 58% received one or more prior salvage therapies. The ORR for O-IVAC was 54.5%. The median duration of study follow-up was 70 months. The median PFS and EFS were 16.3 months each. The median OS was 22.7 months. Age, ECOG performance status and the number of prior therapy lines were independent predictors of survival. Treatment-related mortality was 15.5%. O-IVAC showed a high response rate in a difficult-to-treat population and is an attractive treatment to bridge to potentially curative therapies.

CD14 + HLADR - blood values in patients after alloHSCT are highly predictive of survival and infectious complications.

BACKGROUND: Cytokine storm described in patients after allogeneic haematopoietic stem cell transplantation (alloHSCT) is associated with the appearance of CD14 + HLADR - in the blood. METHODS: To study the role of CD14 + HLADR - cells 223 patients after alloHSCT followed from 1 month to 15 years. The methods used included flow cytometry for blood cells profiling, nucleic acid tests for viral reactivation, and physician care according to the Polish and international guidelines. RESULTS: We found that CD14 + HLADR - peak values determined during the first 60 post-transplant days were higher in the patients who died than in those who survived in this time interval (mean ± SEM: 3.78 ± 0.67% vs 2.38 ± 0.65%, p < 0.001). Receiver operating characteristic (ROC) analysis showed that CD14 + HLADR - cells level in the blood at cut-off point at 0.71% discriminated the patients as to survival; the patients above the threshold had poorer survival (Kaplan-Meier curve covering 15-year observation) than those below (0.19 vs 0.46, p < 0.001). Infections prevailed other causes of death in the high blood CD14 + HLADR - group (0.61 vs 0.38, p = 0.057). ROC analysis defined the CD4+ blood level at 17.70% as not significantly associated with survival. Multivariate analysis revealed that CD14 + HLADR - cells (HR = 3.47, p < 0.001) and the presence of acute graft-versus-host disease (aGvHD) grade ≥ 3 (HR = 3.82, p = 0.005) adversely impacted the survival. CONCLUSIONS: CD14 + HLADR - cells can serve as a biomarker for the risk of fatal complications frequently associated with infections.

Efficacy of daratumumab monotherapy in real-world heavily pretreated patients with relapsed or refractory multiple myeloma.

PURPOSE: Daratumumab is a promising new agent for relapsed/refractory multiple myeloma (RRMM). However, there are limited data on its clinical activity and tolerability in the real-world patients. The purpose of this study is to determine the efficacy and toxicity profile of daratumumab monotherapy in the real-life setting. PATIENTS AND METHODS: Thirty RRMM patients treated with daratumumab who had previously received at least three treatment lines including a proteasome inhibitor and an immunomodulatory drug or had been double refractory (DRMM) were included to the Polish Myeloma Group observational study. RESULTS: The objective response rate to daratumumab was 42.8%. Median progression-free survival (PFS) and overall survival reached 9.5 and 13.8 months, respectively. Importantly, patients with DR-MM had a significantly shorter PFS than other patients (median PFS of 4.1 vs. 12.1 months). Daratumumab was generally well tolerated, however two patients had their therapy interrupted due to adverse events. CONCLUSION: Daratumumab monotherapy has significant activity and good tolerance in heavily pretreated RRMM patients.

Correction: The sorafenib anti-relapse effect after alloHSCT is associated with heightened alloreactivity and accumulation of CD8+PD-1+ (CD279+) lymphocytes in marrow.

[This corrects the article DOI: 10.1371/journal.pone.0190525.].

The sorafenib anti-relapse effect after alloHSCT is associated with heightened alloreactivity and accumulation of CD8+PD-1+ (CD279+) lymphocytes in marrow.

We studied three FLT3 ITD acute myeloid leukemia (AML) patients who relapsed after allogeneic haematopoietic stem cell transplantation (alloHSCT) and received multikinase inhibitor (MKI) sorafenib as part of salvage therapy. MKI was given to block the effect of FLT3 ITD mutation which powers proliferation of blast cells. However, the known facts that sorafenib is more effective in patents post alloHSCT suggested that this MKI can augment the immune system surveillance on leukaemia. In the present study, we investigated in depth the effect of sorafenib on the alloreactivity seen post-transplant including that on leukaemia. The patients (i) responded to the treatment with cessation of blasts which lasted 1, 17 and 42+ months, (ii) developed skin lesions with CD3+ cell invasion of the epidermis, (iii) had marrow infiltrated with CD8+ lymphocytes which co-expressed PD-1 (programmed cell death protein 1 receptor, CD279) in higher proportions than those in the blood (163±32 x103 cells/µl vs 38±8 x103 cells/µl, p<0.001). The Lymphoprep fraction of marrow cells investigated for the expression of genes involved in lymphocyte activation showed in the patients with long lasting complete remission (CR) a similar pattern characterized by (i) a low expression of nitric oxide synthase 2 (NOS2) and colony stimulating factor 2 (CSF2) as well as that of angiopoietin-like 4 (ANGPTL4) (supporting the immune response and anti-angiogenic) genes, and (ii) higher expression of fibroblast growth factor 1 (FGF1) and collagen type IV alpha 3 chain (COL4A3) as well as toll like receptor 9 (TLR9) and interleukin-12 (IL-12) (pro-inflammatory expression profile) genes as compared with the normal individual. The positive effect in one patient hardly justified the presence of unwanted effects (progressive chronic graft-versus-host disease (cGvHD) and avascular necrosis of the femur), which were in contrast negligible in the other patient. The anti-leukemic and unwanted effects of sorafenib do not rely on each other.

Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial.

Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P = .19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P = .64). However, DAC appeared to be superior in the group of patients aged 60-65 (CR rate: DAC 51% vs. DA 29%; P = .02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P = .02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed.

Beneficial effect of the CXCL12-3'A variant for patients undergoing hematopoietic stem cell transplantation from unrelated donors.

The present study aimed to assess the impact of the CXCL12 gene polymorphism (rs1801157) on clinical outcome of hematopoietic stem cell transplantation from unrelated donors. Toxic complications were less frequent among patients transplanted from donors carrying the CXCL12-3'-A allele (42/79 vs. 105/151, p=0.014 and 24/79 vs. 73/151, p=0.009, for grade II-IV and III-IV, respectively). Logistic regression analyses confirmed a role of donor A allele (OR=0.509, p=0.022 and OR=0.473, p=0.013 for grade II-IV and III-IV toxicity). In addition, age of recipients (OR=0.980, p=0.036 and OR=0.981, p=0.040, respectively) was independently protective while female to male transplantation and HLA compatibility were not significant. The incidence of aGvHD (grades I-IV) was lower in patients having A allele (52/119 vs. 113/204, p=0.043) and AA homozygous genotype (6/25 vs. 159/298, p=0.005). Independent associations of both genetic markers with a decreased risk of aGvHD were also seen in multivariate analyses (A allele: OR=0.591, p=0.030; AA homozygosity: OR=0.257, p=0.006) in which HLA compatibility seemed to play less protective role (p<0.1) while recipient age and donor-recipient gender relation were not significant. Moreover, CXCL12-3'-A-positive patients were less prone to early HHV-6 reactivation (2/34 vs. 19/69, p=0.026). The presence of the CXCL12-3'-A variant was found to facilitate outcome of unrelated HSCT.

Anti-CMV-IgG positivity of donors is beneficial for alloHSCT recipients with respect to the better short-term immunological recovery and high level of CD4+CD25high lymphocytes.

Hematopoietic stem cell transplantation from anti-cytomegalovirus immunoglobulin G (anti-CMV-IgG) positive donors facilitated immunological recovery post-transplant, which may indicate that chronic CMV infection has an effect on the immune system. This can be seen in the recipients after reconstitution with donor lymphocytes. We evaluated the composition of lymphocytes at hematologic recovery in 99 patients with hematologic malignancies post hematopoietic stem cell transplantation (HSCT). Anti-CMV-IgG seropositivity of the donor was associated with higher proportions of CD4+ (227.963 ± 304.858 × 106 vs. 102.050 ± 17.247 × 106 cells/L, p = 0.009) and CD4+CD25high (3.456 ± 0.436 × 106 vs. 1.589 ± 0.218 × 106 cells/L, p = 0.003) lymphocytes in the blood at hematologic recovery. The latter parameter exerted a diverse influence on the risk of acute graft-versus-host disease (GvHD) if low (1.483 ± 0.360 × 106 vs. 3.778 ± 0.484 × 106 cells/L, p < 0.001) and de novo chronic GvHD (cGvHD) if high (3.778 ± 0.780 × 106 vs. 2.042 ± 0.261 × 106 cells/L, p = 0.041). Higher values of CD4+ lymphocytes in patients who received transplants from anti-CMV-IgG-positive donors translated into a reduced demand for IgG support (23/63 vs. 19/33, p = 0.048), and these patients also exhibited reduced susceptibility to cytomegalovirus (CMV), Epstein-Barr virus (EBV) and/or human herpes 6 virus (HHV6) infection/reactivation (12/50 vs. 21/47, p = 0.032). Finally, high levels (³0.4%) of CD4+CD25high lymphocytes were significantly associated with better post-transplant survival (56% vs. 38%, four-year survival, p = 0.040). Donors who experience CMV infection/reactivation provide the recipients with lymphocytes, which readily reinforce the recovery of the transplanted patients' immune system.

Role of Donor Activating KIR-HLA Ligand-Mediated NK Cell Education Status in Control of Malignancy in Hematopoietic Cell Transplant Recipients.

Some cancers treated with allogeneic hematopoietic stem cell transplantation (HSCT) are sensitive to natural killer cell (NK) reactivity. NK function depends on activating and inhibitory receptors and is modified by NK education/licensing effect and mediated by coexpression of inhibitory killer-cell immunoglobulin-like receptor (KIR) and its corresponding HLA I ligand. We assessed activating KIR (aKIR)-based HLA I-dependent education capacity in donor NKs in 285 patients with hematological malignancies after HSCT from unrelated donors. We found significantly adverse progression-free survival (PFS) and time to progression (TTP) in patients who received transplant from donors with NKs educated by C1:KIR2DS2/3, C2:KIR2DS1, or Bw4:KIR3DS1 pairs (for PFS: hazard ratio [HR], 1.70; P = .0020, Pcorr = .0039; HR, 1.54; P = .020, Pcorr = .039; HR, 1.51; P = .020, Pcorr = .040; and for TTP: HR, 1.82; P = .049, Pcorr = .096; HR, 1.72; P = .096, Pcorr = .18; and HR, 1.65; P = .11, Pcorr = .20, respectively). Reduced PFS and TTP were significantly dependent on the number of aKIR-based education systems in donors (HR, 1.36; P = .00031, Pcorr = .00062; and HR, 1.43; P = .019, Pcorr = .038). Furthermore, the PFS and TTP were strongly adverse in patients with missing HLA ligand cognate with educating aKIR-HLA pair in donor (HR, 3.25; P = .00022, Pcorr = .00045; and HR, 3.82; P = .027, Pcorr = .054). Together, these data suggest important qualitative and quantitative role of donor NK education via aKIR-cognate HLA ligand pairs in the outcome of HSCT. Avoiding the selection of transplant donors with high numbers of aKIR-HLA-based education systems, especially for recipients with missing cognate ligand, is advisable.

Treatment of elderly patients with acute myeloid leukemia adjusted for performance status and presence of comorbidities: a Polish Adult Leukemia Group study.

This prospective study estimated outcomes in 509 elderly patients with acute myeloid leukemia (AML) with different treatment approaches depending on Eastern Cooperative Oncology Group (ECOG) performance status and Charlson Comorbidity Index (CCI). Patients were stratified into fit (ECOG 0-2 and CCI 0-2) or frail (ECOG>2 and/or CCI>2) groups. Fit patients with CCI 0 received intensive chemotherapy whilst reduced-intensive chemotherapy (R-IC) was given to those with CCI 1-2. Frail patients received best supportive therapy. Fit patients presented a longer overall survival (OS) than frail subjects, but 8-week mortality rates were similar. The complete response (CR) rate between fit CCI 0 and CCI 1-2 subgroups was significantly different. Both of the fit subgroups showed similar 8-week mortality rates and OS probabilities. Allocating fit patients with CCI 1-2 to R-IC enabled an increase in the group of elderly patients who could be treated with the intention of inducing remission.

Donor NK cell licensing in control of malignancy in hematopoietic stem cell transplant recipients.

Among cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), some are sensitive to natural killer (NK) cell reactivity, described as the "missing self" recognition effect. However, this model disregarded the NK cell licensing effect, which highly increases the NK cell reactivity against tumor and is dependent on the coexpression of inhibitory killer cell immunoglobulin-like receptor (iKIR) and its corresponding HLA Class I ligand. We assessed clinical data, HLA and donor iKIR genotyping in 283 patients with myelo- and lymphoproliferative malignancies who underwent HSCT from unrelated donors. We found dramatically reduced overall survival (OS), progression free survival (PFS), and time to progression (TTP) among patients with malignant diseases with the lack of HLA ligand cognate with this iKIR involved in NK cell licensing in corresponding donor (events 83.3% vs. 39.8%, P = 0.0010; 91.6% vs. 47.7%, P = 0.00010; and 30.0% vs. 17.3%, P = 0.013, for OS, PFS, and TTP, respectively). The extremely adverse PFS have withstand the correction when patient group was restricted to HLA mismatched donor-recipient pairs. The incidence of aGvHD was comparable in two groups of patients. In malignant patients after HSCT the missing HLA ligand for iKIR involved in NK cell licensing in corresponding donor ("missing licensing proof") induced extremely adverse survival of the patients due to the progression of malignancy and not to the aGvHD. Avoiding the selection of HSCT donors with the "missing licensing proof" in the malignant patient is strongly advisable.

Donor lymphocyte infusions to leukemic bone lesions are therapeutically effective in a Ph+ ALL patient with post-HSCT relapse.

A Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) case was maintained in remission with the use of chemo-immunotherapy. The latter involved sibling bone marrow transplant (BMT) (three procedures) followed by intravenous (IV) donor lymphocyte infusion (DLI). The third relapse responded to routine chemotherapy and again DLI was employed. During hematological and molecular remission verified at the level of iliac crest aspiration, extra-medullary relapse in the bones was apparent. A novel procedure of donor lymphocyte injection to the bone leukemic lesions was developed and employed. A dose of 10(6) donor lymphocytes/kg body weight (BW) of the recipient were each time injected to the plane of the right and left tibia, the head of the humerus, and the calcaneus, which resulted in healing of the destructive process. In consequence of this novel approach, in addition to the healing of bone lesions, an accumulation of cytotoxic activated T-cells in the marrow was documented, which was mirrored by an increase in the number of transcripts for interferon (IFN)-γ, interleukin (IL)-17, as well as RORγt. The local administration of DLI directly to the leukemic lesions requires a lower dose that diminishes the toxicity due to the general immune system activation.

NOD2/CARD15 single nucleotide polymorphism 13 (3020insC) is associated with risk of sepsis and single nucleotide polymorphism 8 (2104C>T) with herpes viruses reactivation in patients after allogeneic hematopoietic stem cell transplantation.

Three NOD2 polymorphisms (single nucleotide polymorphism [SNP]8 [2104C>T, Arg702Trp], SNP12 [2722G>C, Gly908Arg], and SNP13 [3020insC, Leu1007 fsins C]), identified as disease-associated variants in Crohn's disease, have recently been suggested as gene markers of the outcome of hematopoietic stem cell transplantation (HSCT). In the present multicenter study of 464 donor-recipient pairs, we focused on the effect of NOD2 mutation(s) on the risk of infections and acute graft-versus-host disease (aGVHD). The presence of SNP13 in recipients, donors, or both was more frequently seen in patients having sepsis than in those lacking sepsis (9 of 48 versus 33 of 386, P = .046). The presence of SNP8 (recipient and/or donor positive) was associated with a higher rate of Herpes viruses reactivation (17 of 21 versus 86 of 173, P = .007). In the SNP8-positive group, a trend for a higher rate of bacteremia well controlled by antibiotics was found (9 of 10 versus 47 of 81, P = .106). In contrast, the presence of SNP13 in recipient and/or donor resulted in a poor response to antibiotics (5 of 11 versus 9 of 10, P = .042). A statistically significant association between the presence of NOD2 SNPs and acute grade > II GVHD was found in a subgroup of HSCT patients who received transplants from unrelated donors with a myeloablative conditioning regimen that included antithymocyte globulin (ATG). In this subgroup of patients, donor positivity for any SNPs investigated (7 of 18 versus 17 of 113, P = .036) and, independently, only the presence of SNP8 (4 of 8 versus 20 of 123, P = .055) were associated with severe grade ≥ II aGVHD. In conclusion, SNP8 positivity in donors or recipients makes patients more prone to Herpes viruses reactivation and bacteremia but not to sepsis. Septic complications were associated with SNP13 polymorphism. SNP8 in donors constitutes a risk factor of severe aGVHD, but only if patients received transplants from unrelated donors and received ATG as part of a conditioning regimen.