Lymphomas may be broadly divided into non-Hodgkin (90%) and Hodgkin (10%) types. Most lymphomas (90%) are of B cell origin but can also be T cell or natural killer cell. Clinical management of ...indolent and aggressive lymphomas is different. Aggressive lymphomas are more dangerous if left untreated yet a higher cell proliferation rate also renders them more chemosensitive, so they are managed with curative intent. Indolent lymphomas are, for the most part, incurable, such that quality of life must be balanced against toxicity of treatment in deciding when and how to treat.
Background: Alternative donors permit the application of hematopoietic cell transplantation (HCT) in more than 70% of patients lacking HLA-matched sibling donors (MSDs). Alternative donor sources ...such as matched unrelated donors (MUDs) and umbilical cord blood (UCB) expand the donor pool for allogeneic transplants. However, these donor sources can be associated with higher complication rates and higher costs (Preussler JM et al, Biol Blood Marrow Transplant 2012). Post-transplant cyclophosphamide (PTCy) has facilitated the widespread use of haploidentical donors, and multiple studies report favorable outcomes using this approach. Comparisons of outcomes with this approach however are generally made to MSD or MUD cohorts in whom PTCy was not utilized, and cost comparisons are lacking.
Methods: From March, 2014 through May 2017, all patients considered for allogeneic HCT at Levine Cancer Institute underwent HLA-typing along with their siblings. If no suitable MSD was identified, typing of other family members was performed to identify the most appropriate haploidentical donor. Haploidentical relatives were utilized in patients lacking a suitable MSD. UCB and MUD transplants were not performed. Busulfan/Cy and fludarabine/Cy/TBI were used as myeloablative and non-myeloablative conditioning respectively. All patients received mobilized peripheral blood cells followed by PTCy, tacrolimus and mycophenolate mofetil as GVHD prophylaxis. Disease risk index (DRI) was used to risk stratify patients. This study was designed to compare the outcomes and cost of MSD and haploidentical related donor HCT. Kaplan-Meier method was used to estimate OS and PFS and the differences between MSD and haploidentical were evaluated by log-rank test. Cumulative incidence curves were used to estimate incidences of NRM, with relapse-related mortality as a competing risk, and incidences of acute and chronic GVHD with death from any cause as a competing risk. Group comparison of incidences were determined by Gray's test. Cox regression was used in the multivariate analysis to estimate hazard ratios and corresponding P-values were determined by Wald chi-square test. Differences in major complications between the 2 groups were analyzed using Fisher's exact test.
Results: We performed 59 haploidentical (48 for leukemia, 9 lymphoma and 2 multiple myeloma) and 27 MSD (18 for leukemia, 9 lymphoma) HCTs. The majority of patients received non-ablative conditioning (89.5%). Nine patients received myeloblative chemotherapy (5 in the haploidentical cohort and 4 in the MSD cohort). No significant differences in DRI, recipient age, ABO mismatch, recipient/donor gender were identified between the 2 groups. Donor age was lower in haploidentical (median 38; range 13-72 years), compared with the MSD group (median 56; range 29-73 years; P<0.001). The median follow-up was 17.2 months for the haploidentical group and 20.4 months for the MSD group. The incidences of non-relapse mortality (NRM; P=0.57), overall survival (OS; P=0.63), progression-free survival (PFS; P=0.90), Grades III-IV acute (P=0.56) and chronic GVHD (P=0.86) were similar between the groups (Table 1, figure 1). On multivariate analysis, higher DRI (HR 3.7; P<0.001), older donor age (HR 1.04 per year; P=0.005) and lower Karnofsky score (HR 2.08; P=0.03) were adverse predictors of PFS. Donor source (haploidentical vs. MSD HR 1.46; P=0.36), recipient age, ABO mismatch and donor/recipient gender match were not associated with PFS. No differences in the incidence of significant cardiac, pulmonary, renal, hepatic or GI toxicities were detected between the groups. Inpatient charges and those from the first 100 days following discharge were nearly identical; the median total charges were 0.29% lower in the haploidentical group compared to the MSD group.
Conclusion: This biologically assigned comparison of HCT using haploidentical relatives or MSDs suggests that in patients lacking MSDs, HCT using haploidentical donors yields similar outcomes and incurs similar costs. Validation of these results is warranted.
Display omitted
Trivedi:Pharmacyclics: Consultancy, Honoraria. Ghosh:Seattle Genetics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Jassen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria. Grunwald:ARIAD: Consultancy; Janssen: Research Funding; Cardinal Health: Consultancy; Alexion: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Genentech: Research Funding; Forma Therapeutics: Research Funding; Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Usmani:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Array BioPharma: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Voorhees:Novartis: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy, Speakers Bureau; Oncopeptides: Consultancy; Takeda: Consultancy; Amgen: Speakers Bureau. Bhutani:Prothena Therapeutics: Research Funding; BMS: Speakers Bureau; Amgen: Speakers Bureau; Takeda Oncology: Speakers Bureau.
The T cell receptor (TCR) repertoire of a lymphocyte population may be characterized by the distribution of lengths of the hypervariable fragment known as the complementarity determining region 3 ...(CDR3). Immunological activity leading to clonal predominance will result in an over-representation of given CDR3 lengths and a distortion of the CDR3 length distribution. CDR3 length distribution may be studied by the in vitro amplification of TCRB cDNA followed by gel electrophoresis of the resulting product. We have established a simple, robust method for the evaluation of CDR3 length distribution in human lymphocyte samples. The CDR3 length distribution in phytohaemagglutinin (PHA) activated lymphocytes from a large number of healthy donors was established as a reference panel for each of 22 human TCR beta variable (BV) families. We propose that an abnormal CDR3 length distribution be defined as one in which one or more CDR3 lengths exceed the upper confidence limit (5% significance, one-sided test) given by this PHA reference population. Using this criterion in titration experiments, we were able to identify a clone when it constituted 2% of the cells analyzed. Over-dilution of cellular material or cDNA may produce falsely abnormal CDR3 length distributions. A nested technique using two separate amplification steps was found to yield results comparable in quality to the single amplification technique. When few cells are available, the nested method gives more material for CDR3 length analyses. However, it does not reduce the likelihood of a falsely abnormal distribution being recorded when the cellular material is too scarce.
Bruton's Tyrosine Kinase (BTK) plays a critical role in chronic lymphocytic leukemia (CLL) cell survival by modulating B-cell receptor signaling. Ibrutinib (PCI-32765), a first-in-class oral ...inhibitor of BTK, inhibits proliferation, migration and adhesion in CLL cells. A total of 148 patients with CLL/SLL received ibrutinib monotherapy in a Phase 1 multiple ascending dose study (PCYC-04753) or Phase 1b/2 continuous dosing study (PCYC-1102-CA), after which a long-term extension study was available for continued follow-up for safety and efficacy with daily orally-administered ibrutinib monotherapy. The studies included patients with treatment-naïve (TN) and relapsed or refractory (RR) CLL/SLL. The aims of the present analysis were to evaluate safety based on time on ibrutinib therapy (≤ 1 year and > 1 year), summarize safety findings in the TN and RR patient populations, and assess duration of response (DOR).
Demographics and baseline characteristics were summarized according to parent study, comprising either TN patients or RR CLL/SLL patients who had received at least one dose of ibrutinib monotherapy. Patient disposition, treatment-emergent adverse events (AEs), best response, overall response rate (ORR), and DOR were determined for the time treated (beginning in the parent studies and extending into the long-term extension study).
At a median treatment duration of 21.5 months, 109 out of 148 patients continued treatment with ibrutinib for over a year. The percentage of patients who had a grade 3 or higher serious adverse event (SAE) declined over time from 43% within the first year of study treatment to 32% after the first year of treatment. With respect to side effects determined to be related to study drug, the number of grade 3 AEs and SAEs also declined from within the first year of treatment (24% and 8%, respectively) to after the first year of treatment (7% and 0%, respectively). AEs leading to ibrutinib discontinuation occurred in 12 patients within the first year of treatment for all 148 patients and in 6 out of 109 patients after the first year of treatment.
Overall, the most frequent AEs grade 3 or higher were pneumonia (16.9%), hypertension (13.5%), neutropenia (11.5%), thrombocytopenia (7.4%), and diarrhea (5.4%), regardless of relationship to study drug. Grade 3 or higher SAEs were reported in RR patients at 62% compared to TN patients at 29%. Pneumonia was reported in TN patients at 6.5% and in RR patients at 19.7%.
Within the efficacy population (n = 140), the ORR was 86.2% for TN patients and 88.3% for RR patients who achieved a partial response (PR) or better. The ORR combined with PR with lymphocytosis suggests that 93.1% of TN patients and 93.7% of RR patients achieved an objective response to ibrutinib therapy based on Cheson JCO 2012.
After a median follow up of 27.2 months (range 1.9-42 months) for TN and RR responders who achieved PR or better, the median DOR has not been reached. At landmark 30 months, 76.1% of the responders were alive without progression.
Ibrutinib as a single agent demonstrates long-term safety, tolerability, and durability of response in patients with TN and RR CLL/SLL. Indeed, a decrease in the number of patients experiencing SAEs or AEs grade 3 or higher after 1 year of treatment with ibrutinib resulted in low rates of treatment-related discontinuation after that time point. Grade 3 or higher SAEs were reported at a two-fold higher rate in patients who had received prior therapies, which may be reflective of disease state rather than relationship to ibrutinib. A majority of patients remain on ibrutinib monotherapy with the median DOR not yet reached in the ongoing extension study.
Patient CharacteristicsTreatment-Naïve CLL/SLL (≥ 65 years)Relapsed/Refractory CLL/SLLTotal CLL/SLLNumber of patients31117148Median age (range)71 (65, 84)65 (37, 82)68 (37, 84)Age ≥ 65 years31 (100%)60 (51%)91 (61%)≥ 3 Prior therapies083 (71%)83 (56%)Rai Stage III or IV17 (54%)62 (53%)79 (53%)Median time on study treatment, months (range)26.7 (0.3, 34.0)20.5 (0.3, 42.0)21.5 (0.3, 42.0)Patients continuing study treatment25/ 31 (81%)68/ 117 (58%)93/ 148 (63%)Treatment discontinuation due to disease progression1 (3%)21 (18%)22 (15%)Death within 30 days of last dose011 (9%)11 (7%)
O'Brien:Pharmacyclics: Research Funding. Furman:Genentech: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Gilead: Consultancy. Fowler:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Coutre:Pharmacyclics: Consultancy, Research Funding. Burger:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jones:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wierda:Abbott Laboratories: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, DSMB, DSMB Other, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tragara: Research Funding. Flinn:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding; Janssen: Research Funding. Kolibaba:Pharmacyclics: Research Funding. Shaw:Pharmacyclics: Employment, Equity Ownership. Clow:Pharmacyclics: Employment, Equity Ownership. James:Pharmacyclics: Employment, Equity Ownership. Chu:Pharmacyclics: Employment, Equity Ownership. Byrd:Celgene: Consultancy; Johnson and Johnson: Consultancy; Pharmacyclics: Research Funding.
Optimal hematopoietic stem cell (HSC) mobilization and collection from donors is important for successful allogenic hematopoietic stem cell transplantation (HCT). Plerixafor (Px) can be combined with ...standard use of granulocyte-colony-stimulating factor(G-CSF) in donors with inadequate stem cell mobilization (Gattillo S. et al, Transfusion, 2015). Study in haploidentical transplantation patients showed that addition of Px to G-CSF on day 4 improved PB CD34+ count and harvest. Clinical outcomes including count recovery were similar to the group not requiring Px (Jaiswal et al, Biol Blood Marrow Transplant, 2018). We aimed for a higher CD34+ doses and implemented an algorithm-based approach by adding single dose of Px and extra dose of G-CSF for donors with CD34+ count <20 cells/µL on day 4.
We analyzed our approach on cell composition and transplant outcomes in a cohort of HCT patients biologically assigned matched related (MRD) or haploidentical family donor.
All adult haploidentical or MRD HCT patients at Atrium Health received identical myeloablative (BuCy) or nonmyeloablative (Flu/Cy/TBI) conditioning regimens followed by peripheral blood stem cell grafts and identical PTCy-based regimens for GVHD preventionn were included. Fisher's exact test and two-sample t-test were used. ANC recovery was analyzed by multivariate linear regression.
From March 2014 to September 2018, 128 patients underwent allogenic HCT were included. 22 (17%) donors received plerixafor due to poor mobilization. 13/86 (15%) of haploidentical donors and 9/42 (21%) MRD donors received plerixafor. No significant side effects were observed in donors with Px. Baseline characteristics were similar between patients that received grafts from G-CSF alone and G-CSF and Px donors. The composition of CD4+, CD8+, CD34+ cells (median 6.64 × 106/kg in G alone vs 6.1 × 106/Kg in G+P) were similar between two groups except CD 56+ cells were higher in donors that received G-CSF alone compared to G-CSF and Px 1.42 × 106/Kg vs 1.16 × 106/Kg (P=.002). The time to ANC recovery was significantly shorter in patients receiving grafts from donors that received G-CSF and Px 15 days (range:13-20) compared to G-CSF alone 16 days (10-30) (P=.012) and in Haplo transplant patients 16 days (13-19) vs 17 (12-28) (P=.02). Time to platelet recovery was faster when donors received G-CSF and Px 24 days (16-54) vs G-CSF alone 27 days (16-57) (P=.08). In multivariate analysis Px (β=1.84, 95% CI 0.14-3.55, P= .04) in haploidentical and recipient age <60 yrs (β=2.62, 95% CI 0.11-5.133 P = .05) in MRD patients were associated with faster ANC recovery.
In adults undergoing allogenic transplantations using identical conditioning regimens and PTCy, use of single dose of plerixafor rescue as an adjunct to G-CSF in poorly mobilizing donors resulted in improved CD34+ cell dose and faster ANC recovery.
In HIV‐1‐infected individuals, the CD8+ CD28− T cell subset is considerably expanded and is frequently the largest subset of T cells found in peripheral blood. It has been assumed, but not proven, ...that CD8+ CD28− T cells derive from CD8+ CD28+ T cells in vivo. To further study the ontogeny of CD8+ CD28− T cells, we have performed analyses of the complementarity determining region 3 (CDR3) of the TCRB of CD8+ CD28+ and CD8+ CD28− T cells from the peripheral blood of HIV‐1‐infected individuals. When cells from the same individual were compared, expanded peaks in CDR3 length analysis within a given BV family were frequently observed at the same location in both CD8+ subsets ( p < 0.001). Sequencing of cDNA corresponding to dominant peaks revealed the presence of identical expanded CD8+ T cell clones within both the CD28+ and CD28− subsets on eight of nine attempts. Our results show that CD8+ CD28+ and CD8+ CD28− T cells are phenotypic variants of the same lineage, most likely evolving from CD8+ CD28+ to end‐stage CD8+ CD28− T cells.
To compare the T-cell receptor (TCR) repertoire of T-cell subsets in peripheral blood and lymphoid tissue from HIV-1 infected individuals.
Biopsies of tonsillar tissue and samples of peripheral blood ...were obtained from 10, mostly treatment-naive, HIV-1-infected individuals. CD4 and CD8 T-cell subsets were quantified, the TCR repertoire was analysed within 'naive' and 'memory' subsets, and results compared between identical subsets in tonsillar tissue and blood.
Cell subsets were quantified by flow cytometry. CD4 T cells and CD8 T cells were isolated by immunomagnetic beads. Populations were in most cases further subdivided by immunomagnetic selection on the basis of CD45RO expression. TCR repertoire was studied by spectratyping of the TCR beta variable (BV) complementarity determining region 3 (CDR3) transcripts.
Amongst CD4 T cells, an abnormal TCR repertoire was found in median 25% (range, 0-88%) of BV families in peripheral blood, but in 0% (0-7%) in tonsillar tissue (P<0.05). Large peaks suggestive of expanded clones were common within CD8 T-cells, both in peripheral blood and tonsillar tissue. However, the expanded clones were rarely identical in the two compartments. Expanded CDR3 peaks, suggesting the presence of clonally expanded cells, were observed within both CD45RO+ and CD45RO- cells from all T-cell subsets, but, again they were mainly of different lengths.
CD4 T cells were preserved in number and TCR repertoire in tonsillar tissue compared with blood in HIV-1 infected individuals. T-cells collected from the peripheral blood may not be representative of those residing in lymphoid tissue.
PDF
