Lack of HLA Class I Ligands for Autologous Inhibitory KIR Is Associated with Improved Survival Following Autologous Stem Cell Transplant for Children with Neuroblastoma.

Abstract Background: In hematopoietic stem cell transplantation (HSCT) for hematologic malignancies, natural killer (NK) cells contribute to tumor eradication such that leukemia patients lacking the HLA class I ligand for the donor NK inhibitory killer Ig-like receptors (KIR) have lower relapse rates and longer survival. Since myeloablative chemotherapy followed by autologous HSCT (ASCT) improves survival for children with high risk neuroblastoma (a tumor sensitive to NK killing) we hypothesize that NK cells may be active in this setting and that KIR-HLA combinations where the patient lacks HLA class I ligands for autologous KIR may be associated with improved clinical outcomes. Methods: 155 children with high risk neuroblastoma received myeloablative chemotherapy followed by ASCT between 1992 and 2004. Most patients received anti-GD2 antibody 3F8 and 13-cis-retinoic acid following ASCT. HLA and KIR genotyping was performed. Patients were segregated according to those with or without HLA class I ligand for autologous inhibitory KIR. We examined the 3 inhibitory KIR groups with identified class I ligands: KIR2DL2/2DL3, which recognize HLA-CAsn80(HLA-C1 group), KIR2DL1 recognizing HLA-C Lys80(HLA-C2 group), and KIR3DL1 recognizing HLA-Bw4; as well as 6 activating KIR and 2 KIR haplotype groups. Overall survival and progression-free survival were estimated by Kaplan-Meier method and hazard ratios by Cox regression. No adjustments were made for multiple comparisons. Comparisons of each end point were based on the log-rank statistics. Results: 66% of the 155 children lacked at least 1 HLA ligand for his/ her inhibitory KIR. With median followup of 66.8 months, patients lacking a KIR ligand (n=103) had a 45% lower risk of death compared with patients with all HLA ligands present (n=52) (HR 0.55; 95% CI 0.33–0.90; P=0.015). Similarly, for progression-free survival, the risk of relapse or death was 39% lower for patients lacking an HLA ligand for inhibitory KIR (HR 0.61; 95% CI 0.39–0.97; P=0.035). In particular, patients lacking the HLA-C1 ligand for KIR2DL2/2DL3 experienced an overall survival benefit (HR 0.34; 95% CI 0.11–1.09; P=0.060). Activating KIR and KIR haplotypes were not associated with survival. Conclusion: Among children with high risk neuroblastoma undergoing ASCT, improved overall and progression-free survival is associated with the absence of one or more HLA class I ligands for the patient’s NK cell inhibitory KIR receptor. KIRHLA immunogenetics may therefore be a novel genetic indicator of prognosis for patients undergoing ASCT. Mechanistically, these findings imply that NK tolerance is modified after ASCT, and that KIR-HLA genotypes may also play a role in antibodybased immunotherapy, since most of these patients received 3F8 antibody. These findings require confirmation in a larger prospective study. Figure Figure

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Outcome of Autologous Hematopoietic Stem Cell Transplantation in Relapsed and Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.4626.4626 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4626-4626

Author(s):

Lauren Westfall Veltri ◽

Denái R. Milton ◽

Nina Shah ◽

Krina Patel ◽

Yago Nieto ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Stem Cell ◽

High Risk ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Progression Free Survival ◽

Hemoglobin Level ◽

Hematopoietic Stem ◽

Free Survival

Abstract Introduction: Despite the introduction of highly effective novel agents, the outcome of patients with relapsed and refractory multiple myeloma (RRMM) remains poor, particularly in those with disease refractory to both proteasome inhibitors (PI) and immunomodulatory agents (IMiDs). Limited available data suggests that autologous hematopoietic stem cell transplantation (auto-HCT) may be an effective therapy in this patient population. Methods: We retrospectively analyzed all patients with RRMM who underwent first auto-HCT at our center between March 2000 and October 2015. RRMM was defined as never achieving a response (stable disease [SD]) or having progressed while on therapy or within 60 days after discontinuation of therapy. Patients with disease refractory to at least one PI and at least one IMiD either in combination or administered separately were classified as double refractory (DR-MM). Results: 233 patients with RRMM were identified. Of these, 105 (45%) had DR-MM. The remaining 128 (55%) patients were classified as refractory (R)-MM and included all patients with RRMM but without history of being double refractory. Median age at auto-HCT was 59 years (DR-MM 60 vs. 56 years in R-MM, p=0.005). High-risk cytogenetics (IMWG criteria) were noticed in 67 of 140 (48%) patients (DR-MM, 35/89 [39%] vs. R-MM, 32/51 [63%], p=0.009). Median number of prior lines of therapy was 2 (range 1 - 7) (DR-MM, 2 (1 - 7) vs. R-MM, 1 (1 - 5), p<0.001). Eighty-two (35%) patients received induction with triplet chemotherapy regimens (DR-MM, n=55 [52%] vs. R-MM, n=27 [21%], p<0.001). Chemomobilization was used in 94 (40%) patients (DR-MM, n=54 [51%] vs. R-MM, n=40 [31%], p=0.002). Median time from diagnosis to auto-HCT was 9.4 months (DR-MM 12 vs. 8 months in R-MM, p<0.001). Conditioning regimen consisted of melphalan alone in 168 (72%) and various combinations with melphalan in 65 (28%) patients with no significant difference between DR-MM and R-MM. Maintenance therapy was used in 113 (49%) patients (DR-MM, n=63 [60%] vs. R-MM, n=50 [39%], p=0.001). With a median follow up of 36 months post auto-HCT, at least partial response was seen in 188 (81%) patients (DR-MM, n=83 [79%]; R-MM, n=105 [82%], p=0.50). Near complete remission or better was seen in 52 (22%) patients (DR-MM, n=25 (24%); R-MM, n=27 (21%), p=0.64). The cumulative incidence of non-relapse mortality (NRM) at day 100 and 6 months was 1% and 2% (DR-MM, 0% and 1%; R-MM 2% each at day 100 and 6 months, p=0.56), respectively. The median progression-free survival (PFS) was 17.6 months (14.4 months in the DR-MM and 18.2 months in the R-MM, p=0.40) (Figure 1). Median overall survival (OS) was 48 months (39 months in DR-MM and 57 months in R-MM, p=0.27) (Figure 2). When accounting for other significant measures (i.e., hemoglobin level and β2 microglobulin), having high-risk chromosomal abnormalities was significantly associated with worse PFS (p=0.006) while worsening of PFS for patients with ISS stage II or III disease approached significance (p=0.06). A significant association between OS and hemoglobin level, β2 microglobulin, high risk cytogenetics, ISS stage, and induction treatment was observed, however, none of these measures remained significant in the multivariable model. Conclusions: Our findings highlight that auto-HCT is an effective and safe therapy in patients with RRMM including those who are refractory to an IMiD and PI Figure 1 Progression Free Survival Figure 2. Overall Survival Figure 1. Progression Free Survival Figure 2. Overall Survival Figure 2 Figure 2. Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board.

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Very Low Dose of Anti-T-Lymphocyte Globulin Protects Against Severe Forms of Graft Versus Host Disease in High Risk Patients: The Experience in Our Center

Blood ◽

10.1182/blood-2018-99-118664 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5723-5723

Author(s):

Joan Manuel Mora ◽

Arancha Bermúdez ◽

Miguel Angel Cortés ◽

Yolanda González Romero ◽

Mercedes Colorado ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

High Risk ◽

T Lymphocyte ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Free Survival ◽

Graft Versus Host ◽

Risk Patients

Abstract Background Patients undergoing hematopoietic stem cell transplantation (HSCT) are at high risk of multiple complications being graft versus host disease (GvHD) one of the most concerning. Addition of anti-T-lymphocyte globulin (ATG-Fresenius ®) reduces the incidence of acute and chronic GvHD however, optimal dose has not yet been established. Standard dose (60 mg/kg) has shown a significantly lower moderate-severe cGvHD yet its effect in Progression Free Survival (PFS) and Overall Survival (OS) is contradictory. Our primary objective was to analyze the efficacy of low ATG dose (21 mg/kg) in the prophylaxis of acute and chronic GvHD. As secondary objective we analyzed non-relapse mortality (NRM), infectious and non-infectious complications, GvHD and relapse free survival (GRFS), overall survival and progression free survival in high risk patients undergoing HSCT. Patients and methods We retrospectively analyzed 57 patients who underwent HSCT in our center from 2012 to 2017, receiving a total dose of 21 mg/kg (7 mg/kg on day -3, -2 and -1) of ATG as part of the GvHD prophylaxis, associated to cyclosporine/tacrolimus and MMF/short course-MTX. The conditioning regimen were myeloablative in 42 patients (73.7%). The donor was unrelated in 46 cases (80.7%). Seventeen (29.9%) had a mismatch (16 unrelated, 1 sibling). Stem cell source was peripheral blood in 51 patients (89.4%). Forty six (80.7%) patients were positive for CMV, from these 17 (36.9%) were paired with seronegative donors. The median age was 57 years old (18-70), 38(66.7%) were males. The most frequent diagnosis were Acute Myeloblastic Leukemia (40.4%), myelofibrosis (17.5%) and myelodisplastic syndrome (14%); 28 (49%) had a HCTI score ≥ 3 and 16 (29%) a high risk DRI score. Thirty patients (52.6%) were in complete remission at the moment of HSCT. (Table 1) Results Hematopoietic engraftment was observed in 54 patients (94.7%). The median neutrophil and platelet engraftment were 14 (10-34) and 15 (9-28) days, respectively. Primary graft failure occurred in 3 patients (2 myelofibrosis, 1 AML). Twenty (39.2%) out of 51 evaluable patients developed grade 2-4 acute GvHD. The cumulative incidence of grade 3-4 aGvHD was 8.8% (95% CI, 3.2-17.9%). Skin was the most affected organ (62%). We found a cumulative incidence of moderate to severe cGvHD of 35.2% (95% CI 22.7-47.9%), only 5 cases (10.6%) were severe, with a median onset at day 177 (57-893). The median duration of immunosuppresive systemic therapy was 488 days (207-2046) in the group of patients with moderate to severe cGvHD. Twelve patients died due to transplant related events, 7 were reported before day 100, all of infectious etiology. The NRM at two years was 21.9% (95% CI, 12-33.7%). Eleven patients (19.2%) had at least two episodes of CMV reactivation and one had cytomegalic gastrointestinal disease. One patient developed postransplantation lymphoproliferative disorder associated to Epstein Barr virus. Twenty patients (35%) developed noninfectious complications, being hemorrhagic diathesis, hepatotoxicity and severe mucositis the most frequents. With a median follow up of 28 months in alive patients (3-67), the GRFS at one year, OS and PFS at two years were 47.6% (95% CI, 42.8-52.2%), 59% (95% CI, 54.5-63.2%) and 52% (95% CI, 46.9-56.5%), respectively. The relapse incidence at two years was 26.3% (95% CI 14.7-39.4%). Conclusions In our center, the use of low ATG doses is protective against severe forms of acute GvHD, offering also a moderate protection against chronic GvHD in a cohort with high prevalence of mismatched unrelated donors, high median age and high risk DRI and HCTI. This approach doesn't seem to have a significant negative impact neither in GRFS, OS and PFS at two years. Disclosures No relevant conflicts of interest to declare.

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Outcome of Autologous Stem Cell Transplantation in Myeloma Patients Aged ≥ 75 Years

Blood ◽

10.1182/blood.v128.22.3453.3453 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3453-3453 ◽

Cited By ~ 2

Author(s):

Qaiser Bashir ◽

Mohammed El Shazly ◽

Denái R. Milton ◽

Krina Patel ◽

Nina Shah ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Median Time ◽

Response Rate ◽

Progression Free Survival ◽

Free Survival ◽

Post Transplant

Abstract Introduction Multiple myeloma (MM) is a disease of elderly with median age of diagnosis 66-years. Autologous hematopoietic stem cell transplantation (auto-HCT) is recommended for eligible patients with newly diagnosed MM, however, it is not offered to many elderly patients due to concerns of excessive toxicity. We have previously reported that auto-HCT can be safely performed in myeloma patients aged ≥ 70 years (Bashir et al. L&L 2012). Here we report the results of a retrospective analysis of MM patients aged ≥ 75 years who underwent auto-HCT at our center. Methods All myeloma patients aged ≥ 75 years who underwent auto-HCT at our institution between 1/1/2000 and 12/31/2015 were retrospectively analyzed. Frequencies of toxicities were compared using Fisher's exact test. The cumulative incidence (CI) of non-relapse mortality (NRM) was assessed using the competing risks method. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Differences in survival between groups were assessed using the log-rank test. The association between survival and patient subgroups of interest was determined using univariate and multivariable Cox proportional hazards regression models. Results 72 patients (median age 76 years; 58% male) were included in the study. Thirty percent (n=19/63) were ISS stage I, 43% (n=27/63) were stage II and 27% (n=17/63) stage III. Seventy-eight percent (n=56) were considered standard-risk (IMWG criteria) and 22% (n=16) had high-risk cytogenetics. Sixty-three percent (n=45) received conditioning with melphalan (MEL) 140 mg/m2, while 38% (n=27) received MEL >140. Seventy-five percent (n=54) of the patients received auto-HCT as part of first line therapy and 85% (n=61) had at least partial response (PR) at auto-HCT. Median time from diagnosis to auto-HCT was 7.6 months. Half of the patients (n=36) received post transplant maintenance. Median follow-up time for all survivors (n=48) was 25.5 months. Grade II-IV toxicity was seen in 74% (n=53) of patients, gastrointestinal being most common (49% of all patients). There was no difference in toxicity between MEL 140 vs. MEL >140. The median time to neutrophil and platelet engraftment was 11 and 12 days, respectively. The CI of NRM was 1% at Day 100 and 6 months and 4% at the end of the assessment period. Day 100 response rate (at least PR) was 92% (n=66), with 36% (n=26) achieving near complete remission (nCR) or better. Median PFS was 31.4 months (95% CI: 22.6, 36.6, Figure 1). Seventy-five percent of the patients were event free at one year after transplant and 23% were event free at 5 years. Median OS was 72.8 months (95% CI: 45.7, 86.2, Figure 2). The OS rates at 1 year and 5 years post transplant were 93% and 58%, respectively. On multivariable analysis, high-risk cytogenetics and ISS stage III disease were associated with significantly worse PFS and OS. Conclusion Auto-HCT in myeloma patients aged ≥ 75 years is feasible with response rate and survival comparable to that seen in younger patients. Age alone should not be used to determine eligibility for auto-HCT. Figure 1 Progression-free survival (all patients). Figure 1. Progression-free survival (all patients). Figure 2 Overall survival (all patients). Figure 2. Overall survival (all patients). Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board.

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A Comparative Study of the Outcome of High-Dose Therapy and Autologous Hematopoietic Stem Cell Transplantation in Patients with High-Risk or Standard-Risk Myeloma Treated Concurrently,

Blood ◽

10.1182/blood.v118.21.4156.4156 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4156-4156

Author(s):

Syed Kazmi ◽

Gary Lu ◽

Nina Shah ◽

Qaiser Bashir ◽

Simrit Parmar ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

High Risk ◽

Hematopoietic Stem Cell Transplantation ◽

Maintenance Therapy ◽

Progression Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Standard Risk

Abstract Abstract 4156 Background: Chromosomal abnormalities detected either by conventional cytogenetics (CC) or interphase fluorescence in situ hybridization (FISH) have emerged as important prognostic markers in patients with multiple myeloma (MM) and are used to stratify patients into standard-risk (SR) or high-risk (HR) disease. HR myeloma is associated with shorter remission and survival even with novel agents and autologous hematopoietic stem cell transplantation (auto-HCT). In this report, we describe the outcome of patients with myeloma who received auto-HCT at our institution between January 2008 and December 2009, and had CC and FISH analyses available before auto-HCT to identify HR or SR disease. Methods: Primary objective was to compare the response rate, transplant-related mortality (TRM), time to progression (TTP), progression-free survival (PFS) and overall survival (OS) between HR and SR myeloma. HR myeloma was defined as having deletion of chromosomal 13 or 13q, t(4;14), and del17p by CC; or detection of t(4;14), t(14;16), or del17p by FISH in the bone marrow plasma cells (Munshi, N et al. Blood 2011 117: 4696–4700). Normal or any other CC or FISH abnormalities were considered SR. Response was assessed according to international uniform response criteria for myeloma (BGM Durie et al. Leukemia 2006 20(10):1–7). Kaplan & Meier curves were generated to calculate progression free survival (PFS) and overall survival (OS). Results: Between Jan 2008- Dec 2009, we identified 205 patients, who received auto-HCT at our institution and had pre-transplant CC and FISH analyses available. Twenty-eight patients (14%) had HR while 177 (86%) had SR myeloma. Table 1 summarizes patient characteristics and outcomes for HR and SR patients. Nine HR (30%) and 29 (16%) SR patients had international staging system (ISS) stage III at diagnosis (p=0.04). Twenty-one HR patients (70%) and 91 SR patients (51%) received induction therapy with a bortezomib-based regimen (p=0.01). Thirteen (46%) HR patients and 62 (35%) SR patients received post auto-HCT maintenance therapy (p=0.24). Nineteen HR patients (69%) and 165 SR patients (92%) achieved a CR, VGPR or PR after auto-HCT (p=0.00001). The median follow up in HR and SR patients was 14.5 months (2–30) and 12 months (1–35), respectively. Twenty-two (79%) HR and 46 (25%) SR patients had progressed at last follow up (p=0.00001). Similarly, 12 (43%) HR and 12 (7%) SR patients had died at last follow up (p<0.0001). Median PFS was 9.1 months in HR while it was 30.8 months in SR patients (p=0.000001). Median OS in HR was 19 months while median OS has not yet been reached in SR patients (p=0.000001). In HR patients only the use of maintenance therapy post auto-HCT significantly improved PFS and OS (p=0.001 and p=0.0007, respectively). Conclusion: Patients with HR myeloma had significantly worse outcome than patients with SR disease, even with novel agents and auto-HCT. In HR patients, maintenance therapy was associated with longer PFS and OS. Disclosures: No relevant conflicts of interest to declare.

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Outcome Depend On Age But Not Comorbidity Score, In Patients treated With Fludarabine and Busulfan (FB4) As Conditioning Regimen In Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood.v122.21.4533.4533 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4533-4533

Author(s):

Javier Nunez ◽

Arancha Bermudez ◽

Lucrecia Yanez ◽

Guillermo Martin ◽

Andres Insunza ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

High Risk ◽

Conditioning Regimen ◽

Progression Free Survival ◽

Free Survival ◽

Myeloid Neoplasms ◽

High Risk Disease ◽

Comorbidity Index

Introduction The best conditioning regimen in allogeneic stem cell transplantation (SCT) for myeloid malignancies is unknown. In the last decade, conditioning regimens based on busulfan (BU) and fludarabine (FLU) have shown a good security profile with low early toxicity and mortality but long term follow up is needed to confirm the efficacy in the disease control. Objective To analyze retrospectively the efficacy (overall survival OS, progression free survival PFS) of the conditioning regimen with FLU (40mgr/m2/4 days) and BU (3,2 mgr/kg once daily/4 days) in adult patients with myeloid neoplasms after SCT. Outcome was assessed considering age, comorbidity, disease, and donor. Patients and transplant characteristics Between 2006 and 2012, 90 patients (40 males, 50 females) underwent SCT conditioned with FB4 in our center. The median age of patients was 50 (24-74) years and 34 patients (37%) were older than 55 years. The diagnoses were 65 AML (11 secondary AML and 19 with adverse cytogenetic), 19 MDS (11 with IPSS high/intermediate 2) and 6 MPD (3 CML, 3 myelofibrosis). At time of SCT, 52 patients (80%) with AML were in first CR. High risk disease (secondary AML or with adverse cytogenetic and MDS with high/intermediate IPSS) were considered in 41 patients (45%). The HCT comorbidity index (Sorror) was low, intermediate or high in 20 (22%), 31 (34%) and 39 (43%) patients, respectively. Donor type was matched related in 42 patients (47%), matched unrelated in 30 patients (33%) and mismatched unrelated in 18 patients (20%). Stem cell source were bone marrow in 81 cases (90%). GvHD prophylaxis was done with calcineurin inhibitor associated with short course of methotrexatre or mycophenolate in all patients and Thymoglobulin was administered in 8 patients (9%). Results All patients but one engrafted. The median time to recovery >500 ANC/uL and >50000 platelets/uL was 16 days (range, 9-28) and 16 days (range, 11-455) respectively. Donor complete chimerism was achieved during first or second month in 90% cases. The incidence of acute GVHD grade II-IV and III-IV was 45% and 12% respectively. Chronic GvHD was diagnosed in 60 patients (68%) (26 mild, 18 moderate and 16 severe) and 22 patients (36%) had pulmonary affectation. Transplant related mortality at 100 days and 1 year was 5.5% and 15%. With a median follow up of 26 months (IQL 12-45), the estimated overall survival (OS) was 64% and progression free survival (PFS) was 61%. To be more than 55 years at time of SCT had a negative impact on survival (estimated OS at 40 months: 42% vs 75%, p=0.005). Neither HCT comorbidity index nor disease type had a significant influence on estimated OS at 40 months (70%, 62% and 58% in low, intermediate and high risk) and (64% in AML and 51% in MDS) respectively. However considering the group of high risk disease had worse OS (53% vs 78%, p=0.07). Although there was no significant difference, the OS in mismatched unrelated SCT was worse than matched unrelated and related SCT (40%, 63 % and 71%). Conclusion Conditioning regimen with fludarabine and busulfan (FB4) offers a good effectiveness in patients with myeloid neoplasms and allow the use of myeloablative regimen in patients with high risk disease and significant comorbidities. Only the age at time of SCT had a statically significant impact on overall survival. Disclosures: No relevant conflicts of interest to declare.

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Prophylactic Natural Killer Cell Immunotherapy Following HLA-Haploidentical Hematopoietic Cell Transplantation Prevents Relapse and Improves Survival in Patients with High-Risk Hematological Malignancies

Blood ◽

10.1182/blood.v128.22.1161.1161 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1161-1161 ◽

Cited By ~ 2

Author(s):

Monica Thakar ◽

Parameswaran Hari ◽

David G. Maloney ◽

Carolyn A. Keever-Taylor ◽

Lori Jones ◽

...

Keyword(s):

Overall Survival ◽

T Cell ◽

High Risk ◽

Nk Cells ◽

Hematopoietic Cell Transplantation ◽

Nk Cell ◽

Progression Free Survival ◽

Cell Depletion ◽

T Cell Depletion ◽

Free Survival

Abstract Background: Regimens using post-transplant cyclophosphamide (CY) have been developed to provide potent in vivo T cell depletion for patients undergoing human leukocyte antigen (HLA)-haploidentical hematopoietic cell transplantation (HCT). Luznik, O'Donnell and colleagues (BBMT 2008) reported that when this immune suppression strategy is coupled with non-myeloablative conditioning (fludarabine 150 mg/m2, CY 29 mg/kg, 2 Gy total body irradiation) followed by marrow transplantation, it was well-tolerated with low rates of non-relapse mortality (NRM; 15% at 1 year). However, the 2 year overall survival (OS) and event-free survival were low at 36% and 26%, respectively, due to high relapse rates (51% at 1 year). One explanation could be that while post-HCT CY promoted low rates of acute graft-versus-host disease (GVHD), it also eliminated early T and natural killer (NK) cell clones important for disease surveillance. Based on this hypothesis, we developed a next-generation Phase I/II clinical trial incorporating a boost of donor NK cells on day +7 as an attempt to prevent relapse after transplant. In this study, CY 50 mg/kg as a single dose on day +3 was used for T cell depletion. Methods: Forty patients (pediatric, n=14; adult, n=26) with median age of 45 (range 8-75) years having ALL (n=11), AML (n=9), MDS (n=6), HL (n=6), MM (n=4), NHL (n=3), and CLL (n=1) underwent non-myeloablative transplantation using related, HLA-haploidentical marrow donors on this prospective clinical trial. Patients were high risk due to underlying disease, potential for relapse, and/or risk for transplant-related mortality (TRM). Most patients were heavily pre-treated, with median time from cancer diagnosis to transplant being 2 (0.3 - 12.1) years, including 18 patients having 26 prior HCTs (auto, n=14; allo, n=12). Twenty-five patients (63%) had HCT-CI scores ≥ 3 indicating high risk for TRM. In order to obtain NK cells, non-mobilized peripheral blood mononuclear cells were collected from donors on day +6 using apheresis and stored overnight. NK cells were isolated on day +7 using the Miltenyi CliniMACS system (CD3 depletion followed by CD56 selection) and were administered as a single, fresh infusion that same day without prior culturing or expansion. The Phase I dose-finding study (n=11) enrolled at 2 NK doses [2.5 or 5 x 106/kg +/- 20%, respectively], with extended enrollment at the 2nd dose level for Phase II (n=29) with 83% of patients meeting NK dose parameters. NK cell products had a median log T cell depletion of 5.4 (4.1-7.1), median NK recovery of 54% (33-68%), and median NK purity of 92% (74-99%). Excellent viability (>95%) was seen in all NK products. Results: One patient developed chest pain associated with NK cell infusion; otherwise all other patients tolerated their NK cell infusions well without fevers or other adverse reactions. Full donor chimerism (>95% CD3) was seen in 83% of patients at last follow-up, while 18% and 10% experienced graft rejection or graft failure, respectively. Cumulative incidence of grades 2-3 and grade 3 (no grade 4 seen) acute GVHD occurred in 36% and 8% of patients, respectively, at day +100. Of the 39 evaluable patients, 16% developed chronic extensive GVHD at 1 year. Relapse or progression occurred in 31% of patients by 1 year after HCT. With a median follow-up of 1.5 years (range, 0.1 - 4.9 years), 14 patients have died from relapse/progression (n=11) or infection/VOD (n=3), giving a probability of OS, relapse/progression-free survival (PFS), and NRM at 1 year of 73%, 62%, and 8%, respectively, and 2 year OS and relapse/PFS of 63% and 46%, respectively (Fig 1). Summary: We have demonstrated the safety of infusing donor NK cells early after HCT in a group of heavily-treated patients with high-risk hematological malignancies. In many patients, disease-free survival was possible with the aid of this prophylactic infusion of donor NK cells in combination with allogeneic HCT. These results provide a promising platform to further augment NK cell alloreactivity in the post-HCT setting to prevent relapse and disease progression. Figure 1 Incidence of Overall Survival and Relapse/Progression-Free Survival Figure 1. Incidence of Overall Survival and Relapse/Progression-Free Survival Disclosures Hari: Merck: Research Funding; BMS: Honoraria.

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Multiple Myeloma Patients at Various Cytogenetic Risks Benefit Differently from Autologous Stem Cell Transplantation as a Consolidation Therapy

Stem Cells International ◽

10.1155/2015/613045 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7

Author(s):

Tianmei Zeng ◽

Lili Zhou ◽

Hao Xi ◽

Weijun Fu ◽

Juan Du ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Progression Free Survival ◽

Intermediate Risk ◽

Free Survival

Aim.To evaluate whether patients with multiple myeloma at various risks can still benefit the same from autologous stem cell transplantation consolidation in the era of novel agents. We retrospectively analyzed 67 consecutive myeloma patients receiving autologous stem cell transplantation after bortezomib and/or thalidomide based inductions. Totally 17 high-risk, 24 intermediate-risk, and 26 low-risk patients were enrolled, based on fluorescence in situ hybridization and ISS stage. Meanwhile, another 67 risk-, response depth-, and age-matched patients not proceeding to autologous stem cell transplantation were chosen as controls. Our preliminary data indicated that, in the high-risk subgroup, progression-free survival and overall survival were both significantly prolonged after autologous stem cell transplantation (P<0.001andP=0.015) while, in the intermediate-risk subgroup, neither progression-free survival nor overall survival was prolonged significantly after autologous stem cell transplantation (P>0.05), and in the low-risk subgroup, only progression-free survival was extended significantly (P=0.012) after autologous stem cell transplantation. Multiple variables analysis further indicated that autologous stem cell transplantation and risk stratification were two independent prognostic factors for overall survival. Our results indicated that myeloma patients at different risks all benefit from autologous stem cell transplantation consolidation even in the era of novel agents.

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Plasmablastic Morphology Is an Independent Predictor of Poor Survival After Autologous Stem-Cell Transplantation for Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.1999.17.5.1551 ◽

1999 ◽

Vol 17 (5) ◽

pp. 1551-1551 ◽

Cited By ~ 46

Author(s):

S. Vincent Rajkumar ◽

Rafael Fonseca ◽

Martha Q. Lacy ◽

Thomas E. Witzig ◽

Terry M. Therneau ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Survival Time ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Independent Predictor ◽

Progression Free Survival ◽

Poor Survival ◽

Free Survival

PURPOSE: To study the prognostic value of plasmablastic morphology after autologous stem-cell transplantation for relapsed or primary refractory myeloma. PATIENTS AND METHODS: Seventy-five patients were studied. Investigators blinded to the clinical details of the individual cases reviewed bone marrow aspirate slides to determine plasmablastic classification. Plasmablasts were defined using strict, well-described criteria. Plasmablastic morphology was considered to be present (plasmablastic myeloma) when 2% or more plasmablasts were present in the plasma-cell population. RESULTS: Patients underwent transplantation 5 to 88 months (median, 20 months) after the initial diagnosis of myeloma. Twenty-eight percent of patients had plasmablastic morphology. A significantly greater proportion of patients with plasmablastic morphology had abnormal cytogenetics compared with those with nonplasmablastic classification (73% v 31%, respectively; P = .003). The overall survival rate measured from the time of transplantation was significantly worse in patients with plasmablastic morphology compared with those without (median survival time, 5 months v 24 months, respectively; P < .001). Progression-free survival time was shortened also, with a median time of 4 months compared with 12 months, respectively (P < .001). In the multivariate analysis, plasmablastic classification was the most powerful prognostic factor after transplantation for both overall (P = .001) and progression-free survival rates (P < .001). We also identified three risk groups based on plasmablastic morphology: plasma-cell labeling index, lactate dehydrogenase, and cytogenetics. The median overall survival time was 38 months when none of these factors was abnormal, 17 months with one abnormal factor, and 8 months with two or more abnormal factors (P < .001). CONCLUSION: Plasmablastic morphology is a powerful independent predictor of poor survival rate after autologous stem-cell transplantation for relapsed or primary refractory myeloma.

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Total Body Irradiation, Etoposide, Cyclophosphamide and Autologous Peripheral Blood Stem Cell Transplantation Followed by Randomization to Therapy with Interleukin-2 Versus Observation for Patients with Non-Hodgkin’s Lymphoma: Results of a Phase III Randomized Trial by the Southwest Oncology Group (SWOG 9438).

Blood ◽

10.1182/blood.v108.11.326.326 ◽

2006 ◽

Vol 108 (11) ◽

pp. 326-326 ◽

Cited By ~ 1

Author(s):

John A. Thompson ◽

Richard I. Fisher ◽

Michael L. LeBlanc ◽

Joseph M. Unger ◽

Stephen J. Forman ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Peripheral Blood Stem Cell ◽

Interleukin 2 ◽

Progression Free Survival ◽

High Grade ◽

Survival Estimate ◽

Free Survival ◽

Post Transplant ◽

Total Body

Abstract Purpose: To determine the effect of post-transplant immunotherapy with Interleukin-2 (IL-2) on the progression-free and overall survival of patients with non-Hodgkin’s lymphoma (NHL) after autologous stem cell transplantation and to assess the toxicity of post-transplant IL-2 therapy. Patients and Methods: Patients with previously treated low, intermediate, or high grade NHL (except Working Formulation Groups A and I) were treated with high-dose cyclophosphamide, etoposide, and total body irradiation (TBI) and an autologous peripheral blood stem cell transplant (PBSCT). Twenty-eight to 80 days after PBSCT, patients were randomized to treatment with IL-2 versus observation. Results: Between January 1995 and July 2004, three hundred ninety-four patients with low-grade (n=61) or intermediate-high grade NHL (n=315) were registered at one of 39 SWOG transplant centers. One hundred ninety patients did not proceed to randomization, because of patient refusal (44), grade V toxicity (30), disease progression (28), toxicity (28), or other reasons. Two hundred four patients were randomized to treatment with continuous infusion intravenous IL-2 (9 ×106 units/m2/day for four days followed five days later by 1.6 ×106 units/m2/day for 10 days) versus observation. The 4-year progression-free survival estimate for all eligible patients is 34%, and the 4-year overall survival estimate is 52%. There was no difference in progression-free survival (hazard ratio (HR) of IL-2 to observation = 0.90; p = 0.56) nor in overall survival (HR of IL-2 to observation = 0.88; p = 0.55). There were no deaths related to IL-2 treatment. Grade IV IL-2-related toxicities included hematologic (n=10), cardiovascular (4), renal/bladder (2), flu-like symptoms (1), lung (1), metabolic (1), and neurologic (1) and were reversible in all cases. Conclusions: These results confirm earlier SWOG findings that a regimen of cylophosphamide, etoposide and TBI followed by PBSCT can be administered to patients with relapsed or refractory NHL with acceptable toxicity and with encouraging progression-free and overall survival. Post-transplant therapy with IL-2 given at this dose and schedule of administration had no significant effect on post-transplant relapse, progression-free survival or overall survival.

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The Activating KIR Genes 2DS1 and 2DS2 Regulate NK Alloreactivity In Vitro.

Blood ◽

10.1182/blood.v108.11.927.927 ◽

2006 ◽

Vol 108 (11) ◽

pp. 927-927

Author(s):

Joseph H. Chewning ◽

Charlotte N. Gudme ◽

Bo Dupont

Keyword(s):

Stem Cell ◽

Nk Cells ◽

Hematopoietic Stem Cell ◽

Hla Class I ◽

Class I ◽

Target Cells ◽

Ligand Specificity ◽

Hematopoietic Stem ◽

Allogeneic Hsct

Abstract The role of Natural Killer (NK) cells in host protection against viral infection and malignant transformation has been well described. NK cells may also lead to a reduction in post-transplant relapse and improved survival in hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML). It has been hypothesized that the genotype for the inhibiting killer immunoglobulin-like receptor (KIR) of the hematopoietic stem cell donor in combination with the HLA class I genotype of the recipient could control NK alloreactivity leading to a reduction in post-transplant complications. The KIR gene family encodes however both activating and inhibiting receptors. Here we test the hypothesis that activating KIRs with ligand specificity for HLA class I may contribute to alloreactivity, and potentially could be a genetic factor of significance in allogeneic HSCT. We tested this hypothesis in studies of two pairs of inhibiting and activating KIRs with highly homologous codon sequences in the extracellular domain, namely KIR2DL2/3-KIR2DS2 and KIR2DL1-KIR2DS1. Both the inhibitory 2DL1 and activating 2DS1 have ligand specificity for HLA-Cw group 2, and 2DL2 and 2DL3, have ligand specificity for HLA-Cw group 1, while the activating 2DS2 does not bind in vitro to C1 group. Using an EBV-transformed B-lymphoblastoid cell line (EBV-BLCL) target cell panel homozygous for HLA Class I alleles, we found that NK cells from donors with KIR haplotypes lacking KIR2DS1 or 2DS2 were not cytotoxic to allogeneic EBV-BLCL, independent of the target HLA class I genotype. Polyclonal NK cells obtained from KIR2DS1 positive and C1 group positive donors mediated NK cytotoxicity against C2 positive targets. In contrast, NK cells from KIR2DS1 positive, C2 group homozygous donors displayed minimal cytotoxicity against the C2 group targets (p<0.01). NK clones generated from 2DS1 positive, C2-group negative individuals were cytotoxic to C2-group target cells, while such NK clones could not be obtained from individuals positive for 2DS1 and cognate ligands. Similar findings were made for the relationship between 2DS2, 2DL2/3 and cognate ligand C1 group. Both polyclonal IL-2 propagated NK cells and NK clones from individuals positive for 2DS2 and homozygous for C2 group displayed specific cytotoxicity against C1 positive target cells. The cytotoxicity of 2DS2 positive, C1 group positive NK cells against the C1 positive BLCLs was minimal (p<0.01). These studies demonstrate that 2DS1 and 2DS2 are activating receptors that can induce an alloantigen response. We also present a model for combinations of KIR and HLA genotypes in which the allogeneic function of KIR2DS1 and 2DS2 is consistently seen in donor NK cells. Activating KIR may therefore play a role in allogeneic HSCT, and could contribute to the balance between activating and inhibiting signals for NK cells in HLA-Cw incompatible donor-recipient combinations. Activating KIR interactions with cognate ligand could potentially also play a role in the innate immune response. In the normal host, the increased affinity of the inhibiting KIR isoforms for HLA class I may prevent auto-reactivity, while the activating isoforms may only function in an HLA restricted pattern in context of specific pathogens or transformed cells. It is possible that the low affinity activating KIR may require additional co-stimulating signals that are up-regulated during cellular stress.

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