Increased Infections and Delayed CD4+ T Cell but Faster B Cell Immune Reconstitution after Post-Transplantation Cyclophosphamide Compared to Conventional GVHD Prophylaxis in Allogeneic Transplantation.

Post-transplantation cyclophosphamide (PTCy) is being increasingly used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation (allo-HCT) across various donor types. However, immune reconstitution and infection incidence after PTCy-based versus conventional GVHD prophylaxis has not been well studied. We evaluated the infection density and immune reconstitution (ie, absolute CD4+ T cell, CD8+ T cell, natural killer cell, and B cell counts) at 3 months, 6 months, and 1 year post-HCT in 583 consecutive adult patients undergoing allo-HCT with myeloablative (n = 223) or reduced-intensity (n = 360) conditioning between 2012 and 2018. Haploidentical (haplo; n = 75) and 8/8 HLA-matched unrelated (MUD; n = 08) donor types were included. GVHD prophylaxis was PTCy-based in all haplo (n = 75) and in 38 MUD allo-HCT recipients, whereas tacrolimus/methotrexate (Tac/MTX) was used in 89 and Tac/Sirolimus (Tac/Sir) was used in 381 MUD allo-HCT recipients. Clinical outcomes, including infections, nonrelapse mortality (NRM), relapse, and overall survival (OS), were compared across the 4 treatment groups. The recovery of absolute total CD4+ T-cell count was significantly lower in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups throughout 1 year post-allo-HCT (P = .025). In contrast, CD19+ B-cell counts at 6 months and thereafter were higher in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups (P < .001). Total CD8+ T cell and NK cell recovery was not significantly different among the groups. Infection density analysis showed a significantly higher frequency of total infections in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups (5.0 and 5.0 vs 1.8 and 2.6 per 1000-person days; P < .01) within 1 year of allo-HCT. The cumulative incidence of cytomegalovirus reactivation/infection at 1 year post-allo-HCT was higher in the haplo-PTCy group (51%) compared with the MUD-PTCy (26%), Tac/MTX (26%), or Tac/Sir (13%) groups (P < .001). The incidence of BK, human herpesvirus 6, and other viruses were also higher in the PTCy-based groups. Overall, the treatment groups had similar 2 year NRM (P = .27) and OS (P = .78) outcomes. Our data show that PTCy-based GVHD prophylaxis is associated with delayed CD4+ T cell but faster B cell immune reconstitution and a higher frequency of infections compared with conventional GVHD prophylaxis but has no impact on nonrelapse mortality or overall survival.

Impact of Total Body Irradiation-Based Myeloablative Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation (TBI)-based and chemotherapy only-based myeloablative transplantation conditioning regimens have been applied, but the optimal regimen remains unclear. We performed a systematic review to assess the efficacy of TBI-based versus chemotherapy only-based myeloablative conditioning regimens. We searched PubMed, Embase, and Cochrane databases and meeting abstracts for all studies comparing TBI-based and chemotherapy only-based conditioning regimens in patients who underwent allo-HCT for ALL. Two authors independently reviewed all studies for inclusion and extracted data related to overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD). Eight studies were included in the final analysis. The overall methodological quality of the included studies was optimal. TBI-based regimens showed evidence of benefit compared with chemotherapy only-based conditioning regimens in terms of relapse (relative risk [RR], 0.82; 95% confidence interval [CI], 0.72 to 0.94; 6 studies, 5091 patients), OS (hazard ratio [HR], 0.76; 95% CI, 0.64 to 0.89; 7 studies, 4727 patients), and PFS (HR, 0.74; 95% CI, 0.63 to 0.85; 7 studies, 4727 patients). The TBI-based regimen did not increase the likelihood of grade II-IV acute GVHD (RR, 1.12; 95% CI, 0.92 to 1.36; 5 studies, 4996 patients) or chronic GVHD (RR, 1.10; 95% CI, 1.00 to 1.21; 5 studies, 4490 patients), or NRM (RR, 0.94; 95% CI, 0.69 to 1.28; 6 studies, 4522 patients). However, TBI-based regimens were associated with an increased risk of grade III-IV acute GVHD (RR, 1.29; 95% CI, 1.01 to 1.63; 3 studies, 3675 patients). A subgroup comparison of patients age ≥16 years showed similar results. This systematic review represents evidence supporting the use of TBI-based conditioning regimen in patients undergoing allo-HCT for ALL who are candidates for myeloablative conditioning, as it offers better OS, PFS, and less relapse with acceptable NRM.

A phase 2 trial of GVHD prophylaxis with PTCy, sirolimus, and MMF after peripheral blood haploidentical transplantation.

The introduction of posttransplant cyclophosphamide (PTCy) made performing allogeneic hematopoietic cell transplantation (HCT) from HLA haplotype-incompatible donors possible. In a setting of PTCy and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis, a peripheral blood (PB) graft source as compared with bone marrow reduces the relapse rate but increases acute GVHD (aGVHD) and chronic GVHD (cGVHD). This phase 2 trial assessed sirolimus and MMF efficacy following PTCy as a GVHD prophylaxis after PB haploidentical HCT (haplo-HCT). With 32 evaluable patients (≥18 years) enrolled, this study had 90% power to demonstrate a reduction in 100-day grade II-IV aGVHD to 20% from the historical benchmark of 40% after haplo-HCT using PTCy/tacrolimus/MMF. At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8% (95% confidence interval [CI], 7.5% to 34.0%). There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8% (95% CI, 7.4% to 34.0%), nonrelapse mortality was 18.8% (95% CI, 7.4% to 34.0%), relapse was 22.2% (95% CI, 9.6% to 38.2%), disease-free survival was 59.0% (95% CI, 44.1% to 79.0%), GVHD-free relapse-free survival was 49.6% (95% CI, 34.9% to 70.5%), and overall survival was 71.7% (95% CI, 57.7% to 89.2%) for the entire cohort. These data demonstrate that GVHD prophylaxis with sirolimus/MMF following PTCy effectively prevents grade II-IV aGVHD after PB haplo-HCT, warranting prospective comparison of sirolimus vs tacrolimus in combination with MMF following PTCy as GVHD prophylaxis after PB HCT. This trial was registered at www.clinicaltrials.gov as #NCT03018223.

A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation.

BACKGROUND: There is evidence suggesting that sirolimus, in combination with tacrolimus, is active in the prevention of graft-versus-host disease. Sirolimus-based immune suppression may suppress alloreactive T cells, while sparing the survival and function of regulatory T cells. DESIGN AND METHODS: We conducted a randomized trial to compare the impact of sirolimus/tacrolimus against that of methotrexate/tacrolimus on the prevention of graft-versus-host disease and regulatory T-cell reconstitution. RESULTS: Seventy-four patients were randomized 1:1 to sirolimus/tacrolimus or methotrexate/tacrolimus, stratified for type of donor (sibling or unrelated) and the patients' age. The rate of grade II-IV acute graft-versus-host disease at 100 days was 43% (95% CI: 27-59%) in the sirolimus/tacrolimus group and 89% (95% CI: 72-96%) in the methotrexate/tacrolimus group (P<0.001). The rate of moderate/severe chronic graft-versus-host disease was 24% (95% CI: 7-47%) in the sirolimus/tacrolimus group and 64% (95% CI: 41-79%) in the methotrexate/tacrolimus group (P=0.008). Overall survival and patient-reported quality of life did not differ between the two groups. On days 30 and 90 post-transplant, sirolimus-treated patients had a significantly greater proportion of regulatory T cells among the CD4(+) cells in the peripheral blood, and isolated regulatory T cells were functional. CONCLUSIONS: These data demonstrate that sirolimus/tacrolimus prevents grade II-IV acute graft-versus-host disease and moderate-severe chronic graft-versus-host disease more effectively than does methotrexate/tacrolimus, and supports regulatory T-cell reconstitution following allogeneic hematopoietic cell transplantation.

Fludarabine and pharmacokinetic-targeted busulfan before allografting for adults with acute lymphoid leukemia.

We aimed to evaluate the safety and efficacy of fludarabine (FLU) and pharmacokinetic-targeted busulfan (BU) as conditioning regimen for hematopoietic cell transplantation (HCT) in adult patients with acute lymphoid leukemia (ALL). Forty-four patients with ALL (27 in first complete remission [CR1] and 17 in more advanced disease stage: 4 with primary induction failure [PIF], 12 in CR2, and 1 in CR3) received FLU and pharmacokinetic-targeted BU as preparative therapy for HCT. Grafts were T-replete, filgrastim-mobilized peripheral blood stem cells (PBSC). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (TAC) and short-course methotrexate in 36 patients, TAC and sirolimus in 3, and TAC and mycophenolate mofetil in 5. Primary engraftment was achieved in all 44 patients. The cumulative incidence of transplant-related mortality (TRM) was 2% (95% confidence interval [CI] 0%-16%) at 100 days and 18% (95% CI 10%-34%) at 2 years. The 2-year cumulative incidence of relapse was 19% (95% CI 8%-41%) for those transplanted in CR1, and 48% (29%-80%) for those with more advanced disease. After a median follow-up of 32 months (range: 15-69 months), the 2-year overall survival (OS) was 54% (95% CI 39%-69%). Relapse-free survival (RFS) at 2 years was 63% (95% CI 45%-81%) for patients transplanted in CR1 and 34% (95% CI 11%-57%) for patients transplanted in more advanced disease. When compared to irradiation-containing regimens, FLU and PK-targeted BU appear safer and similarly effective in controlling ALL, providing a treatment option for adult patients with ALL.

A randomized phase II trial comparing tacrolimus and mycophenolate mofetil to tacrolimus and methotrexate for acute graft-versus-host disease prophylaxis.

Tacrolimus (Tac) plus methotrexate (MTX) is a standard regimen for graft-versus-host disease (GVHD) prophylaxis. Mycophenolate mofetil (MMF) is sometimes used instead of MTX to minimize toxicity, despite the lack of controlled studies demonstrating efficacy. We conducted a single-center, randomized phase II trial comparing Tac + MMF to Tac + MTX. Intent-to-treat analyses included 42 patients randomized to Tac + MMF and 47 to Tac + MTX. Patient characteristics were not different between the study arms. Patients in the Tac + MMF arm were less likely to experience severe mucositis, require narcotic analgesia and parenteral nutrition, and had earlier hospital discharge. The Tac + MMF arm had the same time to neutrophil recovery, but earlier platelet recovery. The cumulative incidence of grade II-IV acute GVHD (aGVHD) at 100 days was similar (P = .8), but grade III-IV aGVHD was higher in the Tac + MMF arm (19% versus 4%; P = .03); this was predominantly seen in unrelated donor transplants (26% versus 4%; P = .04), and less in related donor transplants (11% versus 4%; P = n.s.). Moderate or severe chronic GVHD was similar (P = .71). There were no significant differences between the arms in relapse, nonrelapse mortality, or overall and relapse-free survivals. MMF was associated with less early toxicity than MTX but was not as effective in preventing severe aGVHD, especially in unrelated donor transplants.

Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome.

BACKGROUND: Ezatiostat hydrochloride liposomes for injection, a glutathione S-transferase P1-1 inhibitor, was evaluated in myelodysplastic syndrome (MDS). The objectives were to determine the safety, pharmacokinetics, and hematologic improvement (HI) rate. Phase 1-2a testing of ezatiostat for the treatment of MDS was conducted in a multidose-escalation, multicenter study. Phase 1 patients received ezatiostat at 5 dose levels (50, 100, 200, 400 and 600 mg/m2) intravenously (IV) on days 1 to 5 of a 14-day cycle until MDS progression or unacceptable toxicity. In phase 2, ezatiostat was administered on 2 dose schedules: 600 mg/m2 IV on days 1 to 5 or days 1 to 3 of a 21-day treatment cycle. RESULTS: 54 patients with histologically confirmed MDS were enrolled. The most common adverse events were grade 1 or 2, respectively, chills (11%, 9%), back pain (15%, 2%), flushing (19%, 0%), nausea (15%, 0%), bone pain (6%, 6%), fatigue (0%, 13%), extremity pain (7%, 4%), dyspnea (9%, 4%), and diarrhea (7%, 4%) related to acute infusional hypersensitivity reactions. The concentration of the primary active metabolites increased proportionate to ezatiostat dosage. Trilineage responses were observed in 4 of 16 patients (25%) with trilineage cytopenia. Hematologic Improvement-Erythroid (HI-E) was observed in 9 of 38 patients (24%), HI-Neutrophil in 11 of 26 patients (42%) and HI-Platelet in 12 of 24 patients (50%). These responses were accompanied by improvement in clinical symptoms and reductions in transfusion requirements. Improvement in bone marrow maturation and cellularity was also observed. CONCLUSION: Phase 2 studies of ezatiostat hydrochloride liposomes for injection in MDS are supported by the tolerability and HI responses observed. An oral formulation of ezatiostat hydrochloride tablets is also in phase 2 clinical development. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00035867.

Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors.

PURPOSE: To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity. EXPERIMENTAL DESIGN: Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m(2). Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course. RESULTS: Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m(2) dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean V(ss), 2,034 L/m(2)). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses. CONCLUSION: The recommended phase II dose of XRP6258 on this schedule is 20 mg/m(2). The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.

Phase I and pharmacokinetic study of the oral fluoropyrimidine S-1 on a once-daily-for-28-day schedule in patients with advanced malignancies.

PURPOSE: The oral fluoropyrimidine S-1, which consists of a mixture of a 5-fluorouracil (5-FU) prodrug (tegafur), a dihydropyrimidine dehydrogenase inhibitor [5-chloro-2,4-dihydroxypyrimidine (CDHP)], and an inhibitor of orotate phosphoribosyltransferase [potassium oxonate (oxonic acid)], was developed to increase the feasibility and therapeutic index of 5-FU administered orally. The principal objective of this study was to assess the feasibility of administering S-1 on a once-daily-for-28-day schedule every 5 weeks, determine the maximum tolerated dose, characterize the pharmacokinetics of S-1, and seek evidence of anticancer activity. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of S-1 on a once-daily oral schedule for 28 days every 5 weeks. The maximum tolerated dose was defined as the highest dose in which fewer than two of the first six new patients experienced dose-limiting toxicity. The pharmacokinetic profiles of the tegafur, CDHP, and oxonic acid constituents were characterized. RESULTS: Twenty patients were treated with 72 courses of S-1 at three dose levels ranging from 50 to 70 mg/m(2)/day. Diarrhea, which was often associated with abdominal discomfort and cramping, was the principal dose-limiting toxicity of S-1 on this protracted schedule. Nausea, vomiting, mucositis, fatigue, and cutaneous effects were also observed but were rarely severe. Myelosuppression was modest and uncommon. A partial response and a 49% reduction in tumor size were observed in patients with fluoropyrimidine- and irinotecan-resistant colorectal carcinoma. The pharmacokinetic data suggested potent inhibition of 5-FU clearance by CHDP, with resultant 5-FU exposure at least 10-fold higher than that reported from equitoxic doses of tegafur modulated by uracil in the oral fluoropyrimidine UFT. CONCLUSIONS: The recommended dose for Phase II studies of S-1 administered once daily for 28 consecutive days every 5 weeks is 50 mg/m(2)/day. The pharmacokinetic data indicate substantial modulation of 5-FU clearance by CDHP. Based on these pharmacokinetic data, the predictable toxicity profile of S-1, and the low incidence of severe adverse effects at the recommended Phase II dose, evaluations of S-1 on this schedule are warranted in malignancies that are sensitive to the fluoropyrimidines.

Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study.

PURPOSE: To determine the maximum tolerated dose and pharmacokinetics of cantuzumab mertansine, an immunoconjugate of the potent maytansine derivative (DM1) and the humanized monoclonal antibody (huC242) directed to CanAg, intravenously (i.v.) once every 3 weeks and to seek evidence of antitumor activity. PATIENTS AND METHODS: Patients with CanAg-expressing solid malignancies were treated with escalating doses of cantuzumab mertansine administered i.v. every 3 weeks. The pharmacokinetic parameters of cantuzumab mertansine, the presence of plasma-shed CanAg, and the development of both human antihuman and human anti-DM1 conjugate antibodies also were characterized. RESULTS: Thirty-seven patients received 110 courses of cantuzumab mertansine at doses ranging from 22 to 295 mg/m2. Acute, transient, and reversible elevations of hepatic transaminases were the principal toxic effects. Nausea, vomiting, fatigue, and diarrhea were common but rarely severe at the highest dose levels. Dose, peak concentration, and area under the concentration-time curve correlated with the severity of transaminase elevation. The mean (+/- SD) clearance and terminal elimination half-life values for cantuzumab mertansine averaged 39.5 (+/-13.1) mL/h/m2 and 41.1 (+/-16.1) hours, respectively. Strong expression (3+) of CanAg was documented in 68% of patients. Two patients with chemotherapy-refractory colorectal carcinoma had minor regressions, and four patients had persistently stable disease for more than six courses. CONCLUSION: The recommended dose for cantuzumab mertansine is 235 mg/m2 i.v. every 3 weeks. The absence of severe hematologic toxic effects, preliminary evidence of cantuzumab mertansine tumor localization, and encouraging biologic activity in chemotherapy-refractory patients warrant further broad clinical development of this immunoconjugate in CanAg-expressing tumors.

A phase I and pharmacokinetic study of pegylated camptothecin as a 1-hour infusion every 3 weeks in patients with advanced solid malignancies.

PURPOSE: To assess the feasibility of administering camptothecin (CPT), the prototypic topoisomerase I inhibitor, as polyethylene glycol (PEG)-CPT, a macromolecule consisting of CPT conjugated to chemically modified PEG. The study also sought to determine the maximum-tolerated dose (MTD) of PEG-CPT, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of PEG-CPT as a 1-hour intravenous (IV) infusion every 3 weeks. A modified continual reassessment method was used for dose-level assignment to determine the MTD, which was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%. RESULTS: Thirty-seven patients were treated with 144 courses of PEG-CPT at seven dose levels ranging from 600 to 8,750 mg/m(2). Severe myelosuppression was consistently experienced by heavily pretreated (HP) and minimally pretreated (MP) patients at the highest dose level evaluated, 8,750 mg/m(2), whereas both HP and MP patients tolerated repetitive treatment at 7,000 mg/m(2). Cystitis, nausea, vomiting, and diarrhea were also observed but were rarely severe. A partial response was noted in a patient with platinum- and etoposide-resistant small-cell lung carcinoma, and minor responses were noted in one patient each with adenocarcinoma of unknown primary type and osteosarcoma. The pharmacokinetics of free CPT were dose proportional. Free CPT accumulated slowly in plasma, with maximal plasma concentrations achieved at 23 +/- 12.3 hours; the harmonic mean half-life (t(1/2)) of free CPT was long (t(1/2), 77.46 +/- 36.77 hours). CONCLUSION: Clinically relevant doses of CPT can be delivered by administering PEG-CPT. The recommended dose for phase II studies in both MP and HP patients is 7,000 mg/m(2) as 1-hour IV every 3 weeks. The characteristics of the myelosuppressive effects of PEG-CPT, the paucity of severe nonhematologic toxicities with repetitive treatment, the preliminary antitumor activity noted, and the slow clearance of CPT enabling simulation of desirable pharmacokinetic parameters with a convenient single-dosing regimen warrant further disease-directed evaluations.