ALBERT

Description: We have carried out HLA-matched unrelated donor hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning in patients with hematologic malignancies who were ineligible for conventional transplantations because of age, comorbidities, or both. The nonmyeloablative regimen consisted of 90 mg/m2 fludarabine and 2 Gy total body irradiation given before and mycophenolate mofetil and cyclosporine given after HCT. This report compares, retrospectively, morbidity and mortality among 60 consecutive patients given nonmyeloablative conditioning (nonablative patients) to those among 74 concurrent and consecutive patients given myeloablative conditioning (ablative patients) before unrelated HCT. The Charlson Comorbidity Index was used to assess pretransplantation comorbidities. Even though nonablative patients had significantly higher pretransplantation comorbidity scores, were older, and had more often failed preceding ablative transplantations and cytotoxic therapies, they experienced fewer grades III to IV toxicities than ablative patients. Further, the incidence of grades III to IV acute graft-versus-host disease (GVHD) was significantly lower in nonablative patients. Both patient groups had comparable 1-year probabilities of chronic GVHD. The 1-year nonrelapse mortality rate was 20% in nonablative patients compared to 32% in ablative patients (hazard ratio = 1.4). After adjustment for pretransplantation differences between the 2 patient groups, the hazard ratio was 3.0 (P = .04). Multivariate analyses showed higher pretransplantation comorbidity scores to result in increased toxicity and mortality.

Description: Background Post-remission therapies for patients with AML such as high-dose cytarabine (HiDAC) and allogeneic stem cell transplant (alloSCT) have led to improved outcomes for younger patients, but disease recurrence remains prevalent with ~40% 5-year OS. CD33 is a cell surface receptor expressed in ~90% of AML, representing a promising target for therapy. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Methods This phase 1b dose-escalation study (NCT02326584) evaluates the safety and anti-leukemic activity of 33A in combination with consolidation therapy (HiDAC) or as a single agent for maintenance therapy. AML patients (ECOG status 0-1) must be in 1st remission (CR or CRi) after standard induction therapy and be able to receive HiDAC (consolidation cohort) or be in 1st remission and have completed planned post-remission therapies, either chemotherapy and/or alloSCT (maintenance cohort). For maintenance post-alloSCT, patients were between Day 60 and 100 post-transplant without significant GVHD. Prior to HiDAC administration (3 gm/m2 q12h Day 1, 3, 5), 33A is given on Day 1 for up to 4 cycles (28-day cycle). For maintenance therapy, 33A is given as a single agent on Day 1 for up to 8 cycles (6-wk cycle). Results Consolidation cohort: 21 patients (57% male) with a median age of 52 years (range, 21-64) were treated with 5, 10, or 20 mcg/kg of 33A with HiDAC. Patients received a median of 2 cycles (range, 1-4). As anticipated, all patients experienced Grade 4 myelosuppression. At 20 mcg/kg, 1 DLT (lack of recovery of platelets [25K] and/or ANC [500] by Day 42) occurred in Cycle 1. At 10 mcg/kg, no DLTs were observed but delay of subsequent cycles of treatment occurred in 4 of 10 patients, primarily due to thrombocytopenia. No DLTs were observed in the 8 patients treated at 5 mcg/kg and 1 non-hematologic-related dose delay was reported (otitis externa). Non-hematologic treatment-emergent adverse events (AE) in ≥25% of patients regardless of relationship included nausea (38%) and fatigue (33%). No infusion-related reactions (IRRs) or events of veno-occlusive disease were reported. The 30- and 60-day mortality rates were 0%. Of the 19 efficacy evaluable patients, 15 (79%) have maintained remission, 18 patients are alive and 3 patients (14%) remain on treatment. Reasons for treatment discontinuation were completion of planned consolidation therapy (38%), AE (thrombocytopenia, 14%), leukemic relapse (5%), and other non-AE (29%). Nine patients (43%) went on to receive an alloSCT. Maintenance cohort: 22 patients (41% male) with a median age of 45.5 years (range, 23-71) have been treated with 5 mcg/kg of 33A. Patients were a median of 6.2 months from diagnosis (range, 3.4-21.5); 12 patients completed chemotherapy-based treatment alone and 10 patients completed standard chemotherapy with an alloSCT in 1st remission. Patients received a median of 3 cycles (range, 1-6); no DLTs were reported. AEs reported in ≥15% of patients were fatigue (41%), neutropenia (41% [36% ≥G3]), nausea (36%), thrombocytopenia (36% [27% ≥G3]), diarrhea, dyspnea, headache, and vomiting (18% each); no IRRs were observed. Of the 20 efficacy evaluable patients, 15 (75%) have maintained remission. Reasons for treatment discontinuation were AEs (41%, primarily myelosuppression), leukemic relapse (14%), completion of planned therapy (9%), and other non-AE reasons (19%); 4 patients (18%) remain on treatment. Median OS is not yet reached and 19 patients are alive. Pharmacokinetic data in patients receiving post-remission therapy with 33A demonstrate that exposure appears to be greater than in patients with active disease, possibly due to a decrease in target-mediated disposition. Conclusions 33A can be safely administered in combination with HiDAC and as monotherapy in the post-remission setting. In combination with HiDAC, non-hematologic toxicities of 33A were consistent with effects reported with HiDAC alone. As a single agent, 33A administered as maintenance post-chemotherapy and/or alloSCT results in predictable on-target myelosuppression, with mild non-hematologic adverse effects. Disclosures Yang: Seattle Genetics: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Advani:Seattle Genetics: Consultancy, Research Funding. Walter:Emergent Biosolutions: Consultancy; Seattle Genetics: Research Funding; CSL Behring: Research Funding; Celator Pharmaceuticals: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Covagen AG: Consultancy; Agios: Consultancy; Arog: Research Funding. Faderl:Seattle Genetics: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Celator Pharmaceuticals: Research Funding; BMS: Research Funding; Ambit Bioscience: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; JW Pharma: Consultancy; Amgen: Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Erba:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Gylcomimetics: Other: DSMB; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Celator: Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Bexalata: Other: Advisory Board participation. Levy:Amgen: Speakers Bureau; Jansen: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Research Funding. Wood:Pfizer: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement; Juno: Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement. Feldman:Seattle Genetics: Employment, Equity Ownership. Voellinger:Seattle Genetics: Employment, Equity Ownership.

Description: Background: Treatment of elderly AML patients considered unfit for conventional chemotherapy is inadequate and hypomethylating agents are commonly used alternatives. In the case of azacitidine, responses are typically seen after 3–6 cycles of therapy, and a recent large randomized trial in elderly unfit patients reported a complete response (CR)/CR with incomplete blood count recovery rate of 28% (Dombret et al, EHA 2014). Pevonedistat (MLN4924) is an investigational, first-in-class NEDD8-activating enzyme (NAE) inhibitor. A phase 1 trial previously reported pevonedistat single-agent clinical activity in relapsed/refractory AML patients. Preclinical studies of pevonedistat and azacitidine identified synergistic lethality in AML cell lines and murine xenografts. The current phase 1b dose-escalation study evaluated the safety and tolerability of pevonedistat combined with azacitidine in elderly AML patients considered unfit for conventional chemotherapy. Methods: The primary objective was to assess the safety and tolerability of pevonedistat combined with azacitidine. Secondary objectives included assessment of pevonedistat pharmacokinetics (PK) and clinical activity. Treatment-naïve AML patients aged ≥60 years who were considered unfit for standard induction therapy received pevonedistat via 1-hour IV infusion on days 1, 3, and 5 of 28-day cycles. Dose escalation began at 20 mg/m2 and used an adaptive Bayesian continual reassessment method. Azacitidine 75 mg/m2 was administered (IV or SC) on days 1–5 and 8–9. Patients were treated until disease progression or unacceptable toxicity. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Responses were assessed according to International Working Group response criteria for AML. Serial blood samples were obtained for PK analysis following dosing on days 1 and 5 of cycle 1. Results: As of May 30, 2014, 25 patients (median age 75.0 years [range 63–85]; 16 [64%] male) had received pevonedistat 20 mg/m2 (n=22) and 30 mg/m2 (n=3). Primary diagnoses were 16 (64%) de novo AML and 9 (36%) secondary AML. Fourteen (56%) patients had intermediate- and 6 (24%) had adverse-risk cytogenetics (5 [20%] undetermined). During dose escalation, dose-limiting toxicity (DLT) at the 30 mg/m2 pevonedistat dose level included reversible grade 2 increased bilirubin (n=1) and grade 3/4 increased transaminases (n=1) without clinical sequelae. In 1 of the 22 patients treated at the maximum tolerated dose (20 mg/m2 pevonedistat plus 75 mg/m2 IV/SC azacitidine), 1 additional DLT (grade 4 AST/ALT elevation) was seen in the expansion cohort. This patient was successfully re-challenged with a reduced pevonedistat dose. The most common all-grade AEs are shown in table 1. Twelve (48%) patients experienced drug-related grade ≥3 AEs (table 1). The nature and frequency of the reported toxicities (excluding DLTs) were similar to previous reports for azacitidine alone. Preliminary PK data showed that addition of azacitidine did not alter the known PK profile of single-agent pevonedistat. In the 18 response-evaluable patients, there were 6 (33%) CRs and 4 (22%) PRs (table 2), for an overall response rate of 56%. Nine of the 10 responses occurred within the first two cycles of therapy and included 1 patient with bone marrow blasts 〉80%. Conclusions: Combination therapy with pevonedistat and azacitidine was generally well-tolerated. The characteristics of the observed responses suggest added benefit from the addition of pevonedistat compared with azacitidine alone. Table 1 Common all-grade AEs n (%) Most frequent (≥10%) drug-related grade ≥3 AEs n (%) Febrile neutropenia 9 (36) Febrile neutropenia 4 (16) Constipation 8 (32) Thrombocytopenia 3 (12) Decreased appetite 7 (28) – – Thrombocytopenia 7 (28) – – Table 2 Responders* Tumor Type Cytogenetic Risk Group Current Status Response Molecular CR 1st Response 1st CR 1 De novo AML Adverse C12 C4 – – 2 Undetermined C4† C1 C1 Y 3 Adverse C9 C1 C1 Y 4 Undetermined C5‡ C1 C2 Y 5 Intermediate C5† C1 C2 N 6 Intermediate C7 C1 C4 Y 7 Intermediate C2 C2 – – 8 Secondary AML Undetermined C4 C2 C2 – 9 Normal C4 C1 – – 10 De novo AML – C1 C1 – – Molecular CR, complete remission confirmed by molecular studies *All received 20 mg/m2 pevonedistat except #4, who started on 30 mg/m2 and had a dose reduction to 20 mg/m2. †Patient off study ‡Patient off treatment and in follow-up Disclosures Swords: Novartis: Consultancy; KaloBios Pharmaceuticals, Inc.: Consultancy; Millennium: The Takeda Oncology Company: Consultancy. Savona:Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Erba:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding. Foran:Takeda Pharmaceuticals International Co.: Research Funding. Hua:Takeda Pharmaceuticals International Co.: Employment. Faessel:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Dash:Takeda Pharmaceuticals International Co.: Employment. Sedarati:Takeda Pharmaceuticals International Co.: Employment. Dezube:Takeda Pharmaceuticals International Co.: Employment. Medeiros:Millennium: The Takeda Oncology Company: Consultancy, Honoraria; Takeda Pharmaceuticals International Co.: Research Funding.

Description: A hematopoietic cell transplantation (HCT) approach was developed for elderly or ill patients with hematologic malignancies that employed nonmyeloablative conditioning to avoid common regimen-related toxicities and relied on graft-versus-tumor effects for control of malignancy. Eighty-nine patients, median age 53 years, were given fludarabine (90 mg/m2) and 2 Gy total body irradiation. Marrow (n = 18) or granulocyte colony-stimulating factor (G-CSF)–stimulated peripheral blood mononuclear cells (G-PBMCs; n = 71) were transplanted from unrelated donors matched for human leukocyte antigen A (HLA-A), -B, -C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Donor T-cell chimerism was higher for G-PBMCs compared with marrow recipients. Durable engraftment was observed in 85% of G-PBMCs and 56% of marrow recipients. Cumulative probabilities of grade II, III, and IV acute graft-versus-host disease (GVHD) were 42%, 8%, and 2%, respectively. Nonrelapse mortality at day 100 and at 1 year was 11% and 16%, respectively. One-year overall survivals and progression-free survivals were 52% and 38%, respectively. G-PBMC recipients had improved survival (57% vs 33%) and progression-free survival (44% vs 17%) compared with marrow recipients. HLA-matched unrelated donor HCT after nonmyeloablative conditioning is feasible in patients ineligible for conventional HCT. G-PBMCs conferred higher donor T-cell chimerism, greater durable engraftment, and better progression-free and overall survivals compared with marrow.

Description: We previously reported 2-year overall survival (OS) of 60% among 64 pts given nonmyeloablative HCT (Sorror et al, JCO2005, 23: 3819). Here, we update our results on the initial 64 pts with median follow up of 5 (range:3–7) years and report on 18 additional pts with emphasis on: 1) long-term disease control, 2) resolution of chronic GVHD, and 3) outcomes of pts with poor-risk genomic features. Conditioning consisted of 2 Gy total body irradiation with or without fludarabine (90 mg/m2). Median age was 56 (range 42–72) years and median number of prior regimens was 4. Eighty-seven percent, 56%, and 41% of pts had fludarabine-refractory CLL, chemo-resistant disease at HCT, and unfavorable cytogenetics, respectively. Donors were related (n=52) or unrelated (n=30). The incidences of grades II, III, and IV acute GVHD were 39%, 14%, and 2% respectively, and chronic extensive GVHD was 51%. Overall disease response was seen in 70% of pts, and 55% achieved complete remission (CR). Estimated 5-years rates of non-relapse mortality (NRM), progression/relapse, OS, and progression-free survival (PFS) were 23%, 38%, 50%, and 39%, respectively (Table 1 shows outcomes by donor type). Overall, 42 patients are alive; 31 in CR, 4 in PR, 1 with stable disease, and 6 with relapse/progression. Among 14 responding pts tested and found to have molecular eradication of their disease, 2 died of NRM, 2 eventually relapsed, and 10 remained negative at a median of 6 years. Lymph node diameter 〉5 cm was an independent risk factor for relapse (p=0.008) and PFS (p=0.01), while unfavorable cytogenetics (Table 2) were not (p=0.65 and 0.88, respectively). Among the pts who were alive at 5-years, 76% were without chronic GVHD while 24% received immunosuppression for chronic GVHD. Median performance status (PS) was 100% and 90% among pts without or with chronic GVHD, respectively. Nonmyeloablative HCT resulted in a median survival of 5 years for fludarabine-refractory CLL. Sustained molecular remissions and continuing resolution of chronic GVHD with good PS were observed in most pts with extended follow up. Nonmyeloablative HCT might change the natural history of CLL with unfavorable cytogenetics if considered earlier. Table 1: Outcomes by donor type Donor At 5-years Related (n=52) Unrelated (n=30) p-value % % CR 48 67 0.04 NRM 22 24 0.97 Pgrossion/relapse 43 26 0.18 PFS 35 51 0.28 OS 49 51 0.57 Pts alive with chronic GVHD requiring immunosuppression 14 7 Table 2: Outcomes of pts with poor genomic features Abnormality (n) Pts alive Pts who died Median interval, years Median interval, years CR/PR/PD From Dx From HCT CR/PR/NE/PD From Dx From HCT PR indicates partial remission; PD, progression; Dx, diagnosis; and NE, not evaluated del 17p (7) 4/0/0 6.5 3.3 1/0/0/2 6.5 0.3 del 11q (7) 1/2/2 8.1 2.1 1/0/0/1 7.5 0.7 Tri 12 (7) 4/0/0 6.7 4.4 0/0/2/1 3.8 0.2 Complex (9) 4/0/0 11.4 5.7 0/1/0/4 10.5 3.5

Description: Conventional allogeneic hematopoietic cell transplantation (HCT) is effective treatment for AML, but its use has been restricted to younger patients in good medical condition. However, AML is increasingly common with advancing age, and older patients have more adverse prognostic features than younger patients. The vast majority of older patients who reach a CR with chemotherapy relapse within two years from diagnosis and die within three years. The situation is similar in patients with secondary AML or with AML in CR2, more advanced remission status or in partial remission, where median duration of disease-free survival (DFS) is generally

Description: Background: SL-401 is a novel targeted therapy directed to the interleukin-3 receptor (CD123), a target overexpressed on acute myeloid leukemia (AML) blasts and AML cancer stem cells (CSCs), and a variety of additional hematologic malignancies. While conventional chemotherapy can induce remission in a majority of treatment-naive AML patients, relapse rates remain high. Outcomes are particularly poor when minimal residual disease (MRD), as determined by genetic and/or flow cytometric analyses, remains after therapy, with high rates of relapse and short disease-free survival. Conceivably, a therapy directed at lowering MRD burden may improve long-term outcomes. Given the association of MRD with CD123+ AML CSCs, SL-401 is being evaluated in patients with AML in first or second complete remission (CR1 or CR2, respectively) with high risk of relapse including persistent MRD. Preliminary results are reported here. Methods & Results: This multicenter, single-arm Phase 2 trial of AML patients in CR1 or CR2 with high risk of relapse includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients (MRD+ or MRD-) receive SL-401 as a daily IV infusion at 7, 9, or 12 ug/kg/day for days 1- 5 of a 28 day cycle in a 3x3 design. In stage 2, patients (MRD+ only) receive SL-401 at the dose determined in stage 1. Presence of MRD for eligibility requires either molecular (by cytogenetics, FISH, PCR, or next-generation sequencing of AML-associated mutations) or multiparameter flow cytometry (MFC) evidence of persistent abnormalities in the setting of morphologic CR. In stage 2, MRD assessment will include MFC of bone marrow aspirates conducted at a central laboratory for uniformity. Objectives include characterization of SL-401 safety with determination of the maximum tolerated or tested dose, and preliminary assessment of efficacy including changes in MRD burden and response duration. As of 7/27/16, stage 1 has been completed and stage 2 is open for enrollment. Nine patients (stage 1) received SL-401 (7 ug/kg, n=3; 9 ug/kg, n=3; 12ug/kg, n=3). The median age was 63 years (range: 51-78 years); 6 males and 3 females were treated; 8 patients were in CR1 and 1 patient was in CR2 at enrollment. The 12 ug/kg dose level was the highest tested dose with no DLTs; MTD was not reached. The most common treatment-related AEs, all grades, were thrombocytopenia (3/9; 33%) and hypoalbuminemia (3/9; 33%); the most common ≥ grade 3 treatment-related AE was thrombocytopenia (1/9; 11%); there was no DLT. Patients treated at all doses received 1+ to 5+ cycles (ongoing) of SL-401, including 3 MRD+ patients treated at 7 ug/kg (n=1) or 9 ug/kg (n=2) who received 1-5 cycles, and 1 MRD+ patient treated at 12 ug/kg who is receiving ongoing SL-401 for 4+ cycles. For all 3 patients treated at 12 ug/kg (MRD+, n=1; MRD-, n=2), 2 patients remain on SL-401 and have received 1+ and 4+ cycles (both ongoing); one other patient treated at 12 ug/kg discontinued the study because of infection unrelated to study drug. Notably, the one MRD+ patient treated at 12 ug/kg (ongoing at 4+ cycles) had marked MRD reduction as determined by MFC at the local institution; this patient is being considered for stem cell transplant (SCT). Conclusions: Stage 1 is complete without DLT or MTD, and stage 2 (expansion) is open to enroll AML patients in CR1 or CR2 who are MRD+ at the highest tested dose of 12 ug/kg. The safety profile has been similar to that observed in other SL-401 clinical studies, with no unexpected AEs. Targeting MRD with SL-401 has the potential to reduce this chemo-resistant cell population and offer improved long-term outcomes for AML patients in remission with high risk of relapse. Updated data will be presented. Clinical trial information: NCT02270463. Disclosures Lane: N-of-1: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Pfizer: Speakers Bureau; Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau. Wang:Immunogen: Research Funding; Incyte: Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Carraway:Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Lindsay:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Stone:Novartis: Consultancy; Juno Therapeutics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Karyopharm: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

Description: We have shown safety of unrelated donor hematopoietic cell transplantation (HCT) using nonmyeloablative conditioning with fludarabine (FLU, 90 mg/m2) and 2 Gy total body irradiation (TBI) and post-HCT immunosuppression with MMF (15 mg/kg) and cyclosporine (CSP 5–6.25 mg/kg) both given BID (Maris Blood 2003 Vol 102, No 6). The graft rejection rate in the first 89 pts was 23% and more frequent for marrow (8/18; 44%) than PBSC (13/71; 18%) recipients. Multivariate analysis identified recipients of marrow grafts and those without preceding chemotherapy at highest risk for graft rejection (p=0.006 for each). The t½ of mycophenolic acid, the active metabolite of MMF, was 3 hours, and its binding to IMPDH II rapidly reversible. This led to the hypothesis that exclusive use of PBSC grafts and TID dosing of MMF might result in higher engraftment and lower acute GVHD rates. The current protocol (MMF TID) was identical to the original one (MMF BID) except that all pts received PBSC and were given MMF TID. The protocol’s primary goal was to achieve graft rejection

Description: Forty-five patients (pts) with relapsed or chemotherapy refractory low-grade lymphomas were treated with HLA-matched related (n=22) and unrelated (n=23) HCT after nonmyeloablative conditioning using 2 Gy total body irradiation with or without fludarabine. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. Lymphoma histologies included follicular (n=38), small lymphocytic (n=5), and marginal zone (n=2). Seven pts had prior intermediate-grade lymphoma transformation. The median pt age was 54 (range 34–67) years and median time from diagnosis to allogeneic HCT was 4.3 (0.5–18.5) years. Twelve pts had failed and 3 received cytoreductive autologous HCT before nonmyeloablative HCT. Disease status at time of nonmyeloablative HCT included complete remission (CR, n=16), partial remission (PR, n=12), refractory (n=11) and untested relapse (n=6). Prognostic scoring at the time of HCT using the Follicular Lymphoma International Prognostic Index (FLIPI) identified 25 low-risk and 19 intermediate-risk pts and using the International Prognostic Index (IPI) identified 26 low-risk, 13 low-intermediate risk, and 5 intermediate-high risk pts. There were insufficient data to score 1 pt by the FLIPI or by the IPI. All pts received G-CSF mobilzed peripheral blood mononuclear cells. Six of the 23 unrelated donor graft recipients had human leukocyte antigen (HLA) mismatches: one at a single allele, 4 at a single antigen, and one at an antigen and an allele. The median follow up after nonmyeloblative HCT was 23.8 (range 2– 44.9) months. One pt experienced non-fatal graft rejection of a single antigen mismatched unrelated graft. The cumulative probabilities (CP) of acute grades II-IV, III-IV and chronic GVHD were 60%, 18%, and 51%, respectively. Responses [CR (n=14) and PR (n=6)] were seen in 20 of 28 (71%) pts with measurable disease at HCT while 3 had stable and 3 progressive disease, and 2 were not evaluable due to early nonrelapse death. None of the 20 pts who responded and 3 of the 17 transplanted in CR had disease relapse. At 2 years, the CPs of overall relapse/progression, and non-relapse mortality were 15% and 34%, respectively. The 2-year Kaplan-Meier estimates of overall and progression free survival were 58% and 51%, respectively. Higher IPI and FLIPI scores modeled as continuous variables were independently associated with worse PFS (HR 1.55, p=0.05 and HR 1.35, p=0.10 respectively). Use of a HLA mismatched unrelated donor was associated with a trend for worse OS and PFS (HR 3.0, p=0.08 for both). Allogeneic HCT after nonmyeloablative conditioning is a promising salvage strategy for pts with relapsed and refractory indolent lymphoma. The high response and low relapse rates with this approach suggest that relapsed indolent lymphomas are susceptible to graft-versus-tumor responses.

Description: We developed a new HCT-specific comorbidity index (HCT-CI) as a sensitive tool to capture pretransplant comorbidities among pts given allogeneic HCT (Sorror et al. Blood.2005; 106, 2912–2919). Here, we retrospectively analyzed whether the HCT-CI was useful in assessing how pts with B cell malignancies tolerated NM vs M-HCT. Results among consecutive pts (n=125) given NM-conditioning with 2Gy total body irradiation (TBI) (19%) or 2 Gy TBI combined with 90 mg/kg of fludarabine (81%) were compared to those among concurrent M-pts (n=55) conditioned with cyclophosphamide plus busulfan (15%) or 12Gy TBI (85%). Diagnoses were non-Hodgkin lymphoma (NHL, 80% vs 52%), Hodgkin disease (HD, 5% vs 20%), and chronic lymphocytic leukemia (CLL, 15% vs 28%), respectively. At HCT, NM-pts differed substantially from M-pts with respect to age (median 52 vs 40 years,), prior treatment regimens (median 5 vs 3), prior failed high-dose HCT (45% vs 9%), unrelated donors (43% vs 18%), and G-PBMC as stem cell source (99% vs 78%). Smaller differences existed for disease chemo-sensitivity (58% vs 69%) and aggressive disease (56% vs 64%). HCT-CI scores 〉0 were found among 70% and 58% of NM and M-pts, respectively. After HCT, 2-year NRM and survival were 26% and 59% vs 29% and 51% among NM and M-pts, respectively. There were no statistically significant differences in NRM (19% vs 4%, p=0.3) and survival (70% vs 70%, p=0.7) between NM and M-pts with HCT-CI scores of 0; however, this comparison was limited by the small numbers of non-relapse deaths. NM-pts with HCT-CI scores of ≥ 1 had statistically significantly lower NRM (29% vs 47%, HR=0.50, p=0.03, Figure) and better survival (54% vs 37%, HR=0.60 p=0.05) compared to M-pts. These differences remained after adjusting for pretransplant differences (NRM, HR=0.3, p=0.006; survival, HR=0.33, p=0.002). In a further analysis which included all pts, increasing HCT-CI scores and M-conditioning were important risk factors for NRM and survival (Table). We concluded that pts with B cell malignancies and HCT-CI scores of ≥1 tolerated NM-HCT better than M-HCT, and prospective randomized trials may be warranted to confirm this result. Additional data are needed to clarify possible differences between M and NM-conditioning for patients without comorbidities. Table: Multivariate risk factors for HCT outcomes NRM Survival HR p HR p *Lower HR means better survival. Other risk factors, including donor type; CMV sero-status; and disease chemo-sensitivity, were not significant. Conditioning NM 1.0 1.0 M 3.03 0.007 2.27 0.006 HCT-CI scores 0 1.0 1.0 1–2 2.56 1.78 ≥3 3.85 0.001 2.44 0.005 Diagnoses NHL 1.0 1.0 HD 0.79 0.98 CLL 0.55 0.3 0.46 0.03 Graft G-PBMC 1.0 1.0 Marrow 0.23 0.03 0.38 0.03 Age, years