Melhem Solh

Comparison of Outcomes of Hematopoietic Cell Transplants from T-Replete Haploidentical Donors Using Post-Transplantation Cyclophosphamide with 10 of 10 HLA-A, -B, -C, -DRB1, and -DQB1 Allele-Matched Unrelated Donors and HLA-Identical Sibling Donors: A Multivariable Analysis Including Disease Risk Index

Outcomes of 475 consecutive patients undergoing first allogeneic transplantation for hematologic malignancy performed using T-replete HLA-haploidentical donors and post-transplantation cyclophosphamide (HIDT; n = 116) were compared with contemporaneous patients transplanted from 10 of 10 HLA allele-matched unrelated donors (MUDT; n = 178) or HLA-identical sibling donors (MRDT; n = 181). Uniform supportive care measures and assessments were used. Median follow-up was 45 months. HIDT patients were more likely than MUDT patients to be black (44% versus 2%; P < .001). At 2 years after transplantation, estimates of overall survival were 57% for HIDT, 59% for MUDT, and 72% for MRDT (P not significant [NS] for HIDT versus MUDT; P = .02 for HIDT versus MRDT); corresponding disease-free survival rates were 54%, 50%, and 56% (P NS for both comparisons). The respective cumulative incidences (CIs) of nonrelapse mortality were 17%, 16%, 14%, and those of relapse were 29%, 34%, and 30% (P NS for all). The respective CIs of acute graft-versus-host disease (GVHD) grade II-IV were 41%, 48%, and 28% (P = NS for HIDT versus MUDT; P = .005 for HIDT versus MRDT). At 2 years, the respective CIs of moderate/severe chronic GVHD were 31%, 47%, and 44% (P = .004 for HIDT versus MUDT; P = .032 for HIDT versus MRDT) and 19% of HIDT recipients, 42% of MUDT recipients, and 35% of MRDT recipients were on systemic immunosuppressive treatment (P = .007 for HIDT versus MUDT). In recipients of peripheral blood stem cell grafts, the incidence of moderate-severe chronic GVHD was significantly lower in HIDT recipients compared with MUDT recipients (2-year CI, 25% versus 48%; P = .002). In a multivariate analysis incorporating Disease Risk Index and other significant covariates, survival (hazard ratio [HR], 1.31; P = .15) and disease-free survival (HR, 0.96; P = .79) were not significantly different between HIDT and MUDT recipients, but the incidence of chronic GVHD was lower in HIDT recipients (moderate-severe, HR, 0.59; P = .007). HIDT produced similar long-term survival with lower rates of chronic GVHD than optimally matched MUDT. HIDT should be considered a standard of care option for patients lacking a matched sibling donor.

Early Failure of Frontline Rituximab-Containing Chemo-immunotherapy in Diffuse Large B Cell Lymphoma Does Not Predict Futility of Autologous Hematopoietic Cell Transplantation

The poor prognosis for patients with diffuse large B cell lymphoma (DLBCL) who relapse within 1 year of initial diagnosis after first-line rituximab-based chemo-immunotherapy has created controversy about the role of autologous transplantation (HCT) in this setting. We compared autologous HCT outcomes for chemosensitive DLBCL patients between 2000 and 2011 in 2 cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1 year of initial diagnosis. The ERF cohort was compared with those relapsing >1 year after initial diagnosis (late rituximab failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS) of ERF versus LRF cohorts at 3 years were 9% (95% confidence interval [CI], 6% to 13%) versus 9% (95% CI, 5% to 13%), 47% (95% CI, 41% to 52%) versus 39% (95% CI, 33% to 46%), 44% (95% CI, 38% to 50%) versus 52% (95% CI, 45% to 59%), and 50% (95% CI, 44% to 56%) versus 67% (95% CI, 60% to 74%), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk [RR], 1.31; P = .34). The ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR, 2.08; P < .001) and overall mortality (RR, 3.75; P <.001) within the first 9 months after autologous HCT. Beyond this period, PFS and OS were not significantly different between the ERF and LRF cohorts. Autologous HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS, 44%) and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse.

Mobilized Peripheral Blood Stem Cells Versus Unstimulated Bone Marrow As a Graft Source for T-Cell–Replete Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide

Purpose T-cell-replete HLA-haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide was originally described using bone marrow (BM). With increasing use of mobilized peripheral blood (PB), we compared transplant outcomes after PB and BM transplants. Patients and Methods A total of 681 patients with hematologic malignancy who underwent transplantation in the United States between 2009 and 2014 received BM (n = 481) or PB (n = 190) grafts. Cox regression models were built to examine differences in transplant outcomes by graft type, adjusting for patient, disease, and transplant characteristics. Results Hematopoietic recovery was similar after transplantation of BM and PB (28-day neutrophil recovery, 88% v 93%, P = .07; 100-day platelet recovery, 88% v 85%, P = .33). Risks of grade 2 to 4 acute (hazard ratio [HR], 0.45; P < .001) and chronic (HR, 0.35; P < .001) graft-versus-host disease were lower with transplantation of BM compared with PB. There were no significant differences in overall survival by graft type (HR, 0.99; P = .98), with rates of 54% and 57% at 2 years after transplantation of BM and PB, respectively. There were no differences in nonrelapse mortality risks (HR, 0.92; P = .74) but relapse risks were higher after transplantation of BM (HR, 1.49; P = .009). Additional exploration confirmed that the higher relapse risks after transplantation of BM were limited to patients with leukemia (HR, 1.73; P = .002) and not lymphoma (HR, 0.87; P = .64). Conclusion PB and BM grafts are suitable for haploidentical transplantation with the post-transplant cyclophosphamide approach but with differing patterns of treatment failure. Although, to our knowledge, this is the most comprehensive comparison, these findings must be validated in a randomized prospective comparison with adequate follow-up.

Extramedullary Relapse of Acute Myelogenous Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: Better Prognosis Than Systemic Relapse

Allogeneic hematopoietic cell transplantation (HSCT) is considered a curative treatment for acute myelogenous leukemia (AML). Extramedullary relapse after HSCT for AML is a rare event and is less well defined than systemic, hematologic relapse. We retrospectively studied all patients with AML (n = 436) who underwent HSCT at the University of Minnesota between 1996 and 2008 who developed either a bone marrow (BM) or extramedullary (EM) relapse, and examined the incidence and risk factors for BM and EM relapse. Of 128 patients who relapsed post-HSCT, 25 had relapse in EM sites, either isolated (n = 13) or with concurrent BM relapse (n = 12). Relapse sites included bone (n = 1), central nervous system (n = 6), gastrointestinal (n = 4), lymphatic (n = 4), skin (n = 5), genitourinary (n = 1), pulmonary (n = 1), and soft tissue (n = 3). The time to relapse was longer in the EM sites (median, 328 days vs 168 days). Patients with EM relapse were more likely to have had preceding acute graft-versus-host disease (GVHD) (77% vs 49%; P = .03) or chronic GVHD (46% vs 15%; P = .02) compared with those with BM relapse. The 6-month survival postrelapse was significantly better in patients with isolated EM relapse (69%) compared with those with combined EM and BM relapse (8%) or those with BM relapse alone (27%) (P < .01). Compared with local therapy alone, systemic therapy yielded better 6-month survival in patients with EM relapse. This study suggests differing pathogenesis of BM relapse versus EM relapse of AML after allogeneic HSCT. GVHD and its accompanying graft-versus-leukemia effect may better protect BM sites, but patients with EM relapse have better responses to combined therapy and improved survival compared with those with BM relapse.

Late-onset noninfectious pulmonary complications in adult allogeneic hematopoietic cell transplant recipients

Background. Late-onset noninfectious pulmonary complications (LONIPCs) after allogeneic hematopoietic cell transplantation (HCT) contribute to posttransplant mortality, morbidity, and decreased quality of life. The effect of newer HCT approaches including reduced intensity and umbilical cord on the incidence and outcome of LONIPC has not been studied. We hereby present a study evaluating the incidence, risk factors, and outcomes of LONIPC in a recent cohort of allogeneic HCT recipients. Methods. We reviewed the incidence and outcomes of LONIPCs in 451 consecutive adult patients who received allogeneic HCT between 2002 and 2007 and survived for 80 days or more after transplant. Results. Seventy-four patients developed LONIPCs at a median of 177 days (range, 81–1017 days) after HCT. The 1-year cumulative incidence of LONIPCs was 13% (95% confidence interval, 10%–16%). Of the 451 patients, LONIPCs occurred in 21% receiving myeloablative vs. 12% with nonmyeloablative conditioning. Myeloablative conditioning and chronic graft-versus-host disease were associated with significantly higher risks of LONIPC, but age, graft type, and acute graft-versus-host disease were not identified as risk factors. LONIPCs manifest as diffuse alveolar hemorrhage (DAH, n=28), idiopathic pneumonia syndrome (IPS, n=19), bronchiolitis obliterans (n=22), and other uncommon syndromes (n=5). One-year survival was 77% for patients with bronchiolitis obliterans, 37% for patients with IPS, and 36% for patients with DAH. Three-year survival was significantly worse for recipients with LONIPCs compared with those without LONIPCs (34% vs. 57%, P<0.01). Conclusion. LONIPCs in allogeneic HCT recipients include a heterogeneous group of diseases with varying clinical courses and prognosis. LONIPCs, particularly IPS or DAH, are associated with high mortality after HCT.

Platelet and Red Blood Cell Utilization and Transfusion Independence in Umbilical Cord Blood and Allogeneic Peripheral Blood Hematopoietic Cell Transplants

Allogeneic hematopoietic cell transplantation (HCT) recipients have substantial transfusion requirements. Factors associated with increased transfusions and the extent of blood product use in umbilical cord blood (UCB) recipients are uncertain. We reviewed blood product use in 229 consecutive adult recipients of allogeneic HCT at the University of Minnesota: 147 with leukemia, 82 lymphoma or myeloma; 58% received unrelated UCB and 43% sibling donor peripheral blood stem cell (PBSC) grafts. Although neutrophil recovery was prompt (UCB median 17, range: 2-45 days, and PBSC 14, range: 3-34 days), only 135 of 229 (59% cumulative incidence) achieved red blood cell (RBC) independence and 157 (69%) achieved platelet independence by 6 months. Time to platelet independence was prolonged in UCB recipients (median UCB 41 versus PBSC 14 days) and in patients who had received a prior transplant (median 48 versus 32 days). Patients who received UCB grafts required more RBC through day 60 post-HCT (mean UCB 7.8 (95% confidence interval [CI] 6.7-8.9) versus PBSC 5.2 (3.7-6.7) transfusions, P = .04), and more platelet transfusions (mean 25.2 (95% CI 22.1-28.2) versus 12.9 (9.4-16.4), P < .01) compared to PBSC recipients. Patients receiving myeloablative (MA) conditioning required more RBC and platelet transfusions during the first 2 months post-HCT compared to reduced-intensity conditioning (RIC) (7.4 versus 6.2, P = .30 for RBC; 23.2 versus 17.5, P = .07 for platelets). Despite prompt neutrophil engraftment, UCB recipients had delayed platelet recovery as well as more prolonged and costly blood product requirements. Enhanced approaches to accelerate multilineage engraftment could limit the transfusion-associated morbidity and costs accompanying UCB allotransplantation.

Generation of Highly Cytotoxic Natural Killer Cells for Treatment of Acute Myelogenous Leukemia using a Feeder-Free, Particle-Based Approach

Natural killer (NK) cell immunotherapy as a cancer treatment shows promise, but expanding NK cells consistently from a small fraction (∼ 5%) of peripheral blood mononuclear cells (PBMCs) to therapeutic amounts remains challenging. Most current ex vivo expansion methods use co-culture with feeder cells (FC), but their use poses challenges for wide clinical application. We developed a particle-based NK cell expansion technology that uses plasma membrane particles (PM-particles) derived from K562-mbIL15-41BBL FCs. These PM-particles induce selective expansion of NK cells from unsorted PBMCs, with NK cells increasing 250-fold (median, 35; 10 donors; range, 94 to 1492) after 14 days of culture and up to 1265-fold (n = 14; range, 280 to 4426) typically after 17 days. The rate and efficiency of NK cell expansions with PM-particles and live FCs are comparable and far better than stimulation with soluble 41BBL, IL-15, and IL-2. Furthermore, NK cells expand selectively with PM-particles to 86% (median, 35; range, 71% to 99%) of total cells after 14 days. The extent of NK cell expansion and cell content was PM-particle concentration dependent. These NK cells were highly cytotoxic against several leukemic cell lines and also against patient acute myelogenous leukemia blasts. Phenotype analysis of these PM-particle-expanded NK cells was consistent with an activated cytotoxic phenotype. This novel NK cell expansion methodology has promising clinical therapeutic implications.

Core-binding factor acute myeloid leukemia: Heterogeneity, monitoring, and therapy

Core binding factor acute myelogenous leukemia (CBF AML) constitutes 15% of adult AML and carries an overall good prognosis. CBF AML encodes two recurrent cytogentic abnormalities referred to as t(8;21) and inv (16). The two CBF AML entities are usually grouped together but there is a considerable clinical, pathologic and molecular heterogeneity within this group of diseases. Recent and ongoing studies are addressing the molecular heterogeneity, minimal residual disease and targeted therapies to improve the outcome of CBF AML. In this article, we present a comprehensive review about CBF AML with emphasis on molecular heterogeneity and new therapeutic options. Am. J. Hematol. 89:1121–1131, 2014.

Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: Clinical implications for cancer treatment

BACKGROUND AIMS Natural killer (NK) cell immunotherapy for treatment of cancer is promising, but requires methods that expand cytotoxic NK cells that persist in circulation and home to disease site. METHODS We developed a particle-based method that is simple, effective and specifically expands cytotoxic NK cells from peripheral blood mononuclear cells (PBMCs) both ex vivo and in vivo. This method uses particles prepared from plasma membranes of K562-mb21-41BBL cells, expressing 41BBL and membrane bound interleukin-21 (PM21 particles). RESULTS Ex vivo, PM21 particles caused specific NK-cell expansion from PBMCs from healthy donors (mean 825-fold, range 163-2216, n = 13 in 14 days) and acute myeloid leukemia patients. The PM21 particles also stimulated in vivo NK cell expansion in NSG mice. Ex vivo pre-activation of PBMCs with PM21 particles (PM21-PBMC) before intraperitoneal (i.p.) injection resulted in 66-fold higher amounts of hNK cells in peripheral blood (PB) of mice compared with unactivated PBMCs on day 12 after injection. In vivo administration of PM21 particles resulted in a dose-dependent increase of PB hNK cells in mice injected i.p. with 2.0 × 10(6) PM21-PBMCs (11% NK cells). Optimal dose of 800 µg/injection of PM21 particles (twice weekly) with low-dose interleukin 2 (1000 U/thrice weekly) resulted in 470 ± 40 hNK/µL and 95 ± 2% of total hCD45(+) cells by day 12 in PB. Furthermore, hNK cells were found in marrow, spleen, lung, liver and brain (day 16 after i.p. PM21/PBMC injection), and mice injected with PM21 particles had higher amounts. CONCLUSIONS The extent of NK cells observed in PB, their persistence and the biodistribution would be relevant for cancer treatment.

Extramedullary acute myelogenous leukemia

Extramedullary leukemia (EM AML), also known as myeloid sarcoma, is a rare manifestation of acute myelogenous leukemia and often accompanies bone marrow involvement. EM AML is diagnosed based on H&E stains with ancillary studies including flow cytometry and cytogenetics. Isolated EM AML is often misdiagnosed as large cell lymphoma or other lymphoproliferative disorder. The clinical presentation is often dictated by the mass effect and the location of the tumor. The optimal treatment remains unclear. High-dose chemotherapy, radiation, surgical resection, and allogeneic stem cell transplantation are all modalities that can be incorporated into the therapy of EM AML. Cytarabine-based remission induction regimens have been the most commonly used in the upfront setting. There are limited data about the optimal consolidation. Transplantation is ideally offered for high risk disease or in the relapsed setting. In this manuscript, we will review the recent literature about EM AML, focusing on therapy and proposing a treatment algorithm for managing this rare form of leukemia. Further studies addressing risk stratification, role of molecular and genetic aberrations, and optimal treatment strategies are warranted.