Lawrence E. Morris

T-Cell–Replete HLA-Haploidentical Hematopoietic Transplantation for Hematologic Malignancies Using Post-Transplantation Cyclophosphamide Results in Outcomes Equivalent to Those of Contemporaneous HLA-Matched Related and Unrelated Donor Transplantation

PURPOSE T-cell-replete grafts from haploidentical donors using post-transplantation cyclophosphamide may represent a solution for patients who require allogeneic hematopoietic cell transplantation (alloHCT) but lack a conventional donor. We compared outcomes of alloHCT using haploidentical donors with those of transplantation using conventional HLA-matched sibling donors (MRDs) and HLA-matched unrelated donors (MUDs). PATIENTS AND METHODS Outcomes of 271 consecutive patients undergoing T-cell-replete first alloHCT for hematologic malignancies performed contemporaneously at a single center (53 using haploidentical donors; 117, MRDs; 101, MUDs) were compared. Overall and disease-free survival (DFS) were adjusted for effects of significant patient-, disease-, and transplantation-related covariates using a stratified Cox model. RESULTS Patient characteristics were similar between the three donor groups. For patients undergoing MRD, MUD, and haploidentical transplantation, 24-month cumulative incidences of nonrelapse mortality were 13%, 16%, and 7% and of relapse were 34%, 34%, and 33%, respectively (P not significant [NS]). Cumulative incidences of grades 3 to 4 acute graft-versus-host disease (GVHD) at 6 months were 8%, 11%, and 11%, respectively (P NS); extensive chronic GVHD occurred in 54%, 54%, and 38% of patients, respectively (P < .05 for those undergoing haploidentical donor v MRD or MUD transplantation). Adjusted 24-month probabilities of survival were 76%, 67%, and 64% and of DFS were 53%, 52%, and 60%, respectively; these were not significantly different among the three donor groups. CONCLUSION Haploidentical transplantation performed using T-cell-replete grafts and post-transplantation cyclophosphamide achieves outcomes equivalent to those of contemporaneous transplantation performed using MRDs and MUDs. Such transplantation represents a valid alternative for patients who lack a conventional donor.

CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation

Relapse of malignancy after allogeneic hematopoietic cell transplantation (allo-HCT) remains a therapeutic challenge. Blockade of the CTLA4 molecule can effectively augment antitumor immunity mediated by autologous effector T cells. We have assessed the safety and preliminary efficacy of a neutralizing, human anti-CTLA4 monoclonal antibody, ipilimumab, in stimulating the graft-versus-malignancy (GVM) effect after allo-HCT. Twenty-nine patients with malignancies that were recurrent or progressive after allo-HCT, received ipilimumab as a single infusion at dose cohorts between 0.1 and 3.0 mg/kg. Dose-limiting toxicity was not encountered, and ipilimumab did not induce graft-versus-host disease (GVHD) or graft rejection. Organ-specific immune adverse events (IAE) were seen in 4 patients (grade 3 arthritis, grade 2 hyperthyroidism, recurrent grade 4 pneumonitis). Three patients with lymphoid malignancy developed objective disease responses following ipilimumab: complete remission (CR) in 2 patients with Hodgkin disease and partial remission (PR) in a patient with refractory mantle cell lymphoma. At the 3.0 mg/kg dose, active serum concentrations of ipilimumab were maintained for more than 30 days after a single infusion. Ipilimumab, as administered in this clinical trial, does not induce or exacerbate clinical GVHD, but may cause organ-specific IAE and regression of malignancy. This study is registered at (http://clinicaltrials.gov) under NCI protocol ID P6082.

Targeting Vascular Endothelial Growth Factor for Relapsed and Refractory Adult Acute Myelogenous Leukemias: Therapy with Sequential 1-β-d-Arabinofuranosylcytosine, Mitoxantrone, and Bevacizumab

Purpose: Vascular endothelial growth factor (VEGF) promotes acute myelogenous leukemia (AML) cell growth and survival and may contribute to drug resistance. bevacizumab, an anti-VEGF monoclonal antibody, exhibits clinical activity against diverse malignancies when administered with cytotoxic chemotherapy. We conducted a Phase II clinical trial of bevacizumab administered after chemotherapy to adults with refractory or relapsed AML, using a timed sequential therapy (TST) approach. Experimental Design: bevacizumab 10 mg/kg was administered on day 8 after 1-β-d-arabinofuranosylcytosine 2 g/m2/72 h beginning day 1 and mitoxantrone 40 mg/m2 beginning day 4. In vivo laboratory correlates included AML cell VEGF receptor-1 (FLT-1) expression, marrow microvessel density, and free serum VEGF before and during TST with bevacizumab. Results: Forty-eight adults received induction therapy. Myelosuppression occurred in all of the patients similar to other TST regimens. Toxicities were decreased ejection fraction (6%), cerebrovascular bleed (4%), and mortality of 15%. Overall response was 23 of 48 (48%), with complete response (CR) in 16 (33%). Eighteen (14 CR and 4 partial response) underwent one consolidation cycle and 5 (3 CR and 2 partial response) underwent allogeneic transplant. Median overall and disease-free survivals for CR patients were 16.2 months (64%, 1 year) and 7 months (35%, 1 year). Marrow blasts demonstrated FLT-1 staining before bevacizumab and marked decrease in microvessel density after bevacizumab. VEGF was detected in pretreatment serum in 67% of patients tested, increased by day 8 in 52%, and decreased in 93% (67% undetectable) 2 h after bevacizumab. Conclusions: In this single arm study, cytotoxic chemotherapy followed by bevacizumab yields a favorable CR rate and duration in adults with AML that is resistant to traditional treatment approaches. The clearance of marrow blasts in some patients after bevacizumab suggests that VEGF neutralization might result directly in leukemic cell death. The potential biological and clinical activity of bevacizumab in AML warrants additional clinical and laboratory study.

Haploidentical Transplantation Using T Cell Replete Peripheral Blood Stem Cells and Myeloablative Conditioning in Patients with High-Risk Hematologic Malignancies Who Lack Conventional Donors is Well Tolerated and Produces Excellent Relapse-Free Survival: Results of a Prospective Phase II Trial

Haploidentical hematopoietic stem cell transplant (HSCT) provides an opportunity for nearly all patients to benefit from HSCT. We conducted a trial of haploidentical T cell replete allografting using a busulfan-based myeloablative preparative regimen, peripheral blood stem cells (PBSCs) as the graft source, and posttransplantation cyclophosphamide (Cy). Eligibility was limited to patients at high risk of relapse after nonmyeloablative haploidentical bone marrow transplant (BMT). Twenty patients were enrolled in the study (11 with relapsed/refractory disease and 9 who underwent transplantation while in remission and considered standard risk). Donor engraftment occurred in all 20 patients with full donor T cell and myeloid chimerism by day +30. The cumulative incidence of grades II-IV and III-IV acute graft-versus-host disease (aGVHD) was 30% and 10%, respectively. The cumulative incidence of chronic GVHD (cGVHD) was 35%. Nonrelapse mortality (NRM) at 100 days and 1 year was 10% for all patients and 0% for standard-risk patients. With a median follow-up of 20 months, the estimated 1-year overall survival (OS) and disease-free survival (DFS) was 69% and 50%, respectively, for all patients, and 88% and 67% for standard-risk patients. Myeloablative haploidentical HSCT is associated with excellent rates of engraftment, GVHD, NRM, and DFS, and is a valid option in patients with high-risk malignancies who lack timely access to a conventional donor.

Nonmyeloablative HLA-Haploidentical Bone Marrow Transplantation with High-Dose Posttransplantation Cyclophosphamide: Effect of HLA Disparity on Outcome

Although some reports have found an association between increasing HLA disparity between donor and recipient and fewer relapses after allogeneic blood or marrow transplantation (BMT), this potential benefit has been offset by more graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). However, the type of GVHD prophylaxis might influence the balance between GVHD toxicity and relapse. The present study analyzed the impact of greater HLA disparity on outcomes of a specific platform for nonmyeloablative (NMA), HLA-haploidentical transplantation. A retrospective analysis was performed of 185 patients with hematologic malignancies enrolled in 3 similar trials of NMA, related donor, haploidentical BMT incorporating high-dose posttransplantation cyclophosphamide for GVHD prophylaxis. No significant association was found between the number of HLA mismatches (HLA-A, -B, -Cw, and -DRB1 combined) and risk of acute grade II-IV GVHD (hazard ratio [HR] = 0.89; P = .68 for 3-4 vs fewer antigen mismatches). More mismatching also had no detrimental effect on event-free survival (on multivariate analysis, HR = 0.60, P = .03 for 3-4 vs fewer antigen mismatches and HR = 0.55, P = .03 for 3-4 vs fewer allele mismatches). Thus, greater HLA disparity does not appear to worsen overall outcome after NMA haploidentical BMT with high-dose posttransplantation cyclophosphamide.

Single Cycle of Arsenic Trioxide–Based Consolidation Chemotherapy Spares Anthracycline Exposure in the Primary Management of Acute Promyelocytic Leukemia

PURPOSE Event-free survival following all-trans-retinoic acid (ATRA) -based therapy for acute promyelocytic leukemia (APL) averages 70% at 5 years. While arsenic trioxide (ATO) can induce remissions in 95% of relapsed patients, few studies have addressed the integration of ATO into the primary management of APL. This study examines the efficacy of a single cycle of ATO-based consolidation therapy in a treatment regimen designed to decrease exposure to other cytotoxic agents. PATIENTS AND METHODS After induction with ATRA and daunorubicin (DRN), untreated patients with APL received 3 days of cytarabine and DRN followed by 30 doses of ATO beginning on day 8. Molecular remitters received 2 years of risk-based maintenance therapy. Results Forty-one of 45 patients receiving induction therapy achieved remission; four patients died (one before treatment was initiated). Thirty-seven patients received consolidation and maintenance; of these one patient relapsed (CNS) and one died in remission during maintenance therapy (hepatic sickle cell crisis). With a median follow-up of 2.7 years, estimated disease-free survival was 90%; overall survival for all patients was 88%. Despite a total anthracycline dose of only 360 mg/m(2), cardiac ejection fraction decreased by > or = 20% in 20% of patients. CONCLUSION These data, combined with other recent studies using ATO in the primary management of APL, demonstrate the important role that ATO can play in the primary management of this curable disease. Future studies should continue to focus on reducing the toxicity of treatment without increasing the relapse rate.

Total Body Irradiation-Based Myeloablative Haploidentical Stem Cell Transplantation Is a Safe and Effective Alternative to Unrelated Donor Transplantation in Patients Without Matched Sibling Donors.

We enrolled 30 patients on a prospective phase II trial utilizing a total body irradiation (TBI)-based myeloablative preparative regimen (fludarabine 30 mg/m2/day × 3 days and TBI 150 cGy twice per day on day -4 to -1 [total dose 1200 cGy]) followed by infusion of unmanipulated peripheral blood stem cells from a haploidentical family donor (haplo). Postgrafting immunosuppression consisted of cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil through day 35, and tacrolimus through day 180. Median patient age was 46.5 years (range, 24 to 60). Transplantation diagnosis included acute myelogenous leukemia (n = 16), acute lymphoblastic leukemia (n = 6), chronic myelogenous leukemia (n = 5), myelodysplastic syndrome (n = 1), and non-Hodgkins lymphoma (n = 2). Using the Dana Farber/Center for International Blood and Marrow Transplant Research/Disease Risk Index (DRI), patients were classified as low (n = 4), intermediate (n = 12), high (n = 11), and very high (n = 3) risk. All patients engrafted with a median time to neutrophil and platelet recovery of 16 and 25 days, respectively. All evaluable patients achieved sustained complete donor T cell and myeloid chimerism by day +30. Acute graft-versus-host disease (GVHD) grades II to IV and III and IV was seen in 43% and 23%, respectively. The cumulative incidence of chronic GVHD was 56% (severe in 10%). After a median follow-up of 24 months, the estimated 2-year overall survival (OS), disease-free survival (DFS), nonrelapse mortality, and relapse rate were 78%, 73%, 3%, and 24%, respectively. Two-year DFS and relapse rate in patients with low/intermediate risk disease was 100% and 0%, respectively, compared with 39% and 53% for patients with high/very high risk disease. When compared with a contemporaneously treated cohort of patients at our institution receiving myeloablative HLA-matched unrelated donor (MUD) transplantation (acute myelogenous leukemia [n = 17], acute lymphoblastic leukemia [n = 15], chronic myelogenous leukemia [n = 7], myelodysplastic syndrome [n = 7], non-Hodgkin lymphoma [n = 1], chronic lymphoblastic leukemia [n = 1]), outcomes were statistically similar, with 2-yr OS and DFS being 78% and 73%, respectively after haplo transplantation versus 71% and 64%, respectively, after MUD transplantation. In patients with DRI low/intermediate risk disease, 2-yr DFS was superior after haplo compared with MUD transplantations (100% versus 74%, P = .032), whereas there was no difference in DFS in patients with high/very high risk disease (39% versus 37% for haplo and MUD respectively, P = .821). Grade II to IV acute GVHD was seen less often after haplo compared with MUD transplantation (43% versus 63%, P = .049), as was moderate-to-severe chronic GVHD (22% versus 58%, P = .003). Myeloablative haplo transplantation using this regimen is a valid option for patients with advanced hematologic malignancies who lack timely access to a conventional donor. Outcomes appear at least equivalent to those seen in contemporaneous patients who underwent transplantation from MUD.

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.

Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide

The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.

Phase II trial of tipifarnib as maintenance therapy in first complete remission in adults with acute myelogenous leukemia and poor-risk features.

Purpose: Acute myelogenous leukemia (AML) does not have a high cure rate, particularly in patients with poor-risk features. Such patients might benefit from additional therapy in complete remission (CR). Tipifarnib is an oral farnesyltransferase inhibitor with activity in AML. We conducted a phase II trial of maintenance tipifarnib monotherapy for 48 adults with poor-risk AML in first CR. Experimental Design: Tipifarnib 400 mg twice daily for 14 of 21 days was initiated after recovery from consolidation chemotherapy, for a maximum of 16 cycles (48 weeks). Results: Twenty (42%) patients completed 16 cycles, 24 (50%) were removed from study for relapse, and 4 (8%) discontinued drug prematurely for intolerance. Nonhematologic toxicities were rare, but tipifarnib dose was reduced in 58% for myelosuppression. Median disease-free survival (DFS) was 13.5 months (range, 3.5-59+ months), with 30% having DFS >2 years. Comparison of CR durations for 25 patients who received two-cycle timed sequential therapy followed by tipifarnib maintenance with 23 historically similar patients who did not receive tipifarnib showed that tipifarnib was associated with DFS prolongation for patients with secondary AML and adverse cytogenetics. Conclusions: This study suggests that some patients with poor-risk AML, including patients with secondary AML and adverse cytogenetics, may benefit from tipifarnib maintenance therapy. Future studies are warranted to examine alternative tipifarnib dosing and continuation beyond 16 cycles.