ALBERT

Description: Radioimmunotherapy (RIT) is a useful addition to the armamentarium against NHL. Due to concerns about chronic myelosuppression and the possible inability to mobilize stem cells or tolerate further therapy after RIT, this modality has not been commonly utilized in potential transplant candidates. We report the successful mobilization, collection, transplantation and engraftment of 5 patients with NHL following yttrium-90 ibritumomab tiuxetan. Patients had follicular lymphoma, grade I or II (n=3), transformed follicular lymphoma (n=1) or blastic variant mantle cell lymphoma (n=1). Time from RIT to mobilization was 10 months (median; range 7–27 months). The median number of regimens prior to RIT was 2.5 (range 1–4) including prior autologous transplant (n=1). The median number of regimens following RIT and prior to transplant was 1.5 (range 1–2). All patients exhibited chemosensitive disease. Patients were mobilized with R-ICE/G-CSF (n=4) or G-CSF alone (n=1) and required 2.8 leukaphereses (mean; range 2–5). The CD34 yield was 3.8x106 CD34+ cells/kg (median; range 3.4–5.1x106 CD34+ cells/kg). All patients received busulfan, VP-16, ARA-C and cyclophosphamide (BVAC) as the preparatory regimen. One patient received IL-2 from day 0 to day 11. Time to engraftment was 13 days (median; range 9–19 days) for an absolute neutrophil count (ANC) 〉500 cells/ml and 23 days (median; range 15–44 days) for a platelet count〉20x103/ml. The patient on the IL-2 study showed delayed engraftment of both ANC (day 19) and platelets (day 27). The patient with mantle cell lymphoma, who was undergoing his second autologous transplant, exhibited delayed platelet engraftment (day 44). Time to engraftment did not differ significantly for either ANC (p=0.16) or platelets (p=0.10) in 18 RIT-naïve NHL patients receiving BVAC and an autologous peripheral blood stem cell transplant (PBSC) during the same time period. There were no treatment-related deaths. With a median follow up of 12 months, one patient has died of disease recurrence. Two patients remain in complete remission. Two patients are alive with disease (relapse at 12 months and 14 months) and are currently receiving therapy. No patient has demonstrated laboratory or cytogenetic evidence of a myelodysplastic syndrome. In conclusion, heavily pretreated patients who have received radioimmunotherapy with yttrium-90 ibritumomab tiuxetan and subsequently relapse can successfully undergo mobilization, collection, and autologous PBSC transplant. These patients demonstrate full engraftment, durable remissions and tolerate additional therapy should relapse occur following transplant.

Description: Autologous stem cell transplant is an effective modality for many patients with lymphoproliferative disorders. Still, the majority of patients with myeloma and many with lymphoma relapse after transplant. Innovative post-transplant immunotherapies are needed. We initiated a phase I immune mobilization trial utilizing dose escalation of IL-2, in combination with GM-CSF and G-CSF, in an attempt to mobilize autologous cytotoxic effector cells, along with peripheral CD34+ hematopoietic progenitor cells. IL-2 began on day 0 of mobilization and continued as a daily SQ injection for 11 days. On day 7 of mobilization, GM-CSF (7.5 mcg/kg/d) and G-CSF (5 mcg/kg/d) were initiated for 5 days (day 7–11). On day 11, leukapheresis was performed. Patients then received melphalan (200 mg/m2) followed by reinfusion of cryopreserved autologous peripheral hematopoietic progenitor cells. Phenotypic and functional analyses were performed using peripheral blood mononuclear cells (PBMNC) collected during mobilization on days 0, 7 and 11. Eleven of 12 patients treated to date completed the regimen (myeloma, n=11; NHL, n=1). One patient (NHL) was removed due to progressive disease. The first two dose levels of IL-2 have been well tolerated (dose level 1: 6x105 IU/m2/d; n=6 pts; dose level 2: 1x106 IU/m2/d; n=6 pts) with no ≥grade 3 toxicities noted. Dose escalation of IL-2 continues since the MTD has not been reached. Phenotypic analyses of PBMNC demonstrate an increase in CD3+CD8+ T cells from 17.5% (day 0 baseline) to 22.7% (day 11; p = 0.01). CD56+ NK cells increased from 18.9% (day 0) to 36.0% (day 11; p = 0.002), and CD8+CD56+ NKT cells increased from 8.2% (day 0) to 18.0% (day 11; p = 0.01). Cytotoxicity directed against a human myeloma cell line using peripheral blood lymphocytes was 8.6% at baseline and increased to 43% on day 11 of mobilization (p=0.03). All patients successfully mobilized and received an autologous transplant without delay in engraftment (ANC recovery: day 13 median; range 10–14 days; platelet recovery: day 12 median; range of 0–13 days). These results are encouraging and demonstrate effective mobilization with minimal toxicity and marked in vivo immunomodulatory effects. In addition, the enhanced cytotoxic effector cell number and killing of myeloma cells is quite promising, with additional follow up ongoing to determine the potential impact on survival.

Description: Elderly patients with AML (〉60) have a poor prognosis due to high risk cytogenetics and a high incidence of secondary AML. Comorbid conditions make induction therapy more risky and less effective. There is a need for less toxic and more effective treatment for these patients. The combination of bortezomib (B) and melphalan (M) demonstrate synergistic cytotoxicity in vitro against AML cell lines providing a rationale for this combination in patients with AML. We report the initial results of a pilot study of low-dose M and B for the treatment of patients with AML and high-risk myelodysplastic syndromes. Eligibility requirements included a diagnosis of AML or high-risk MDS and subjects were not candidates for standard induction therapy or had failed therapy. Strata 1 included patients who had received no previous therapy and strata 2 patients with refractory or relapsed disease. Treatment consisted of M (2mg) oral daily dose and B (1.0mg/M2) on day 1, 4, 8 &11 of a 28 day cycle. Ten patients have been enrolled. Median age was 69 (range 54–79), 8 patients w/ AML and 2 w/ refractory MDS. Five patients were previously treated (strata 2); regimens included induction (7(3), auto SCT (1) and azacytadine (2). Cytogenetic abnormalities were present in 70% of patient specimens. To date 25 cycles of treatment have been given (range 1–6). Six patients are evaluable for response. Two patients (both with MDS) were withdrawn after 1 cycle for cytopenias. Two patients with AML achieved CR by bone marrow morphology. One patient, a 78 year old man with multiple cytogenetic abnormalities and no previous treatment achieved remission with normalization of cytogentetics after 4 cycles. A 74 year old man who had failed previous therapy for his AML achieved a morphologic remission with persistent cytogenetic abnormalities after 6 cycles. Three patients required admission for management of febrile episodes in association with neutropenia that were disease related. There were no treatment related admissions or grade 3/4 non hematologic toxicity events. The 74 year old man who achieved a CR with no “in hospital” days while on study had previously failed to respond to two induction attempts which required a 44 day hospitalization. Accrual continues. In summary, the combination of low dose oral melphalan with low dose bortezomib appears to be a novel, active and well tolerated outpatient treatment for elderly patients with high risk MDS and AML.