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BACKGROUND In an ECOG-ACRIN Cancer Research Group study (E1496), maintenance rituximab (MR) was reported to prolong progression-free survival (PFS) in comparison with observation (OBS) alone in patients with indolent lymphoma after induction chemotherapy. Here the long-term follow-up of the same patient cohort is presented. METHODS Patients with indolent lymphoma received induction chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP). Patients with stable disease or a better response were then randomized to weekly rituximab (375 mg/m2 × 4 doses) every 6 months for 2 years (MR) or to OBS. The primary endpoint was PFS; the secondary endpoints were overall survival (OS), response rate, and toxicities. RESULTS Of the 387 patients who initially received CVP induction, 158 were randomized to MR, and 153 were randomized to OBS. After a median follow-up of 11.5 years, patients on MR had longer median PFS (4.8 years) than patients on OBS (1.3 years; hazard ratio [HR], 0.49; P < .0001). However, there was no difference in OS between MR and OBS (10-year OS, 67% vs 59%; median OS, 13.5 years vs not reached; HR, 0.91; P = .69). Other than MR, only minimal residual disease after induction therapy was significantly associated with PFS on multivariate analysis (HR, 0.71; P = .02). A low initial tumor burden, minimal residual disease, follicular histology, a low Follicular Lymphoma International Prognostic Index score, and female sex were associated with longer OS. There was no increase in the rate of second primary malignancies with MR vs OBS. CONCLUSIONS With long-term follow-up, MR did not influence OS. The PFS benefit was maintained. MR should be considered optional for patients with indolent B-cell lymphoma. Cancer 2016;122:2996-3004. © 2016 American Cancer Society.

Background Evans syndrome (ES) is characterized by the simultaneous or sequential presence of multiple autoimmune cytopenias. It is often secondary to rheumatologic disorders or lymphoid malignancies, but has not previously been associated with babesiosis. Here we present two cases of severe cytopenias in asplenic patients precipitated by active babesiosis. Case Report The first patient had a history of Hodgkin's lymphoma in remission and autoimmune hemolytic anemia (AIHA) treated by splenectomy 12 years prior who presented with severe AIHA and thrombocytopenia after Babesia infection. The second patient had a history of ES requiring splenectomy, which relapsed after Babesia infection. Results The complex presentation and medical histories of both patients made the diagnosis challenging. Both patients’ cytopenias responded to therapy, although the use of immunosuppressive agents in patients with active hematologic infections was challenging and required a multidisciplinary approach. Conclusion These two cases illustrate the possibility of babesiosis to not only reactivate ES in asplenic patients, but also precipitate increased levels of immune deregulation, potentially provoking ES, a phenomenon not previously reported.

BACKGROUND: ABVD with or without radiation is standard therapy for limited stage HL, but carries risks of bleomycin-lung injury and radiation toxicity. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate which is highly active in relapsed classical HL. We previously combined BV with AVD in limited stage non-bulky classical HL which resulted in a high CR rate, but at the cost of increased neutropenia, neutropenic fever, and neuropathy, likely related to the overlapping toxicity profile with vinblastine. Similar toxicity findings were also observed with BV-AVD in advanced stage classical Hodgkin lymphoma. We therefore evaluated BV plus AD (BV-AD) without radiation therapy for non-bulky stage I-II classical HL with the goal of reducing toxicity and maintaining high rates of inducing CR. METHODS: This is a multicenter single arm open label phase 2 study. Patients received BV 1.2 mg/kg plus standard dose adriamycin and dacarbazine on days 1 and 15 of each 28 day cycle. GCSF prophylaxis was not included. Patients received 4 or 6 cycles of BV-AD based on the results of an interim PETCT scan performed following cycle 2. PET negativity was defined as Deauville scores 1-3. Patients in CR on interim PETCT received 4 total cycles of therapy; patients in PR completed 6 cycles. The primary endpoint is complete response rate (CRR) at end of treatment. A sample size of 34 was required to detect an end of treatment CRR of 95% with 91% power and alpha error of 0.09. RESULTS: 34 patients were enrolled. Median age is 36 (range 18-63). Stage is IA (3), IB (1), IIA (29) and IIB (1). Risk is classified per the GHSG criteria as early unfavorable in 47%, and favorable in 53%. The interim CR rate is 94%. Accordingly, 32 interim PET negative patients (94%) received 4 total cycles of therapy, and 2 interim PET positive patients (6%) received 6 total cycles of therapy. No patients received consolidative radiation therapy, per protocol. The primary endpoint of end of treatment CR rate is 100%. At a median follow-up of 15 months, the FFS, PFS and OS are all 100%. The most common adverse events of any grade are nausea (79%), peripheral sensory neuropathy (56%), fatigue (50%), constipation (38%), alopecia (35%) and neutropenia (24%). Most toxicities were low grade, with only 15% of subjects experiencing any grade 3 toxicity, and there were no grade 4 or 5 toxicities. Specifically, 2 patients had grade 3 neutropenia, and 1 patient each had grade 3 nausea/vomiting, pneumonia and thromboembolic event. Peripheral sensory neuropathy was grade 1 in 17 patients, and grade 2 in 2 patients. There were no cases of neutropenic fever. CONCLUSIONS: BV-AD for 4-6 cycles induces high interim and end of treatment CR rates of 94% and 100%, respectively, allowing 4 total cycles of therapy in most patients. The PFS, FFS and OS are all 100% at last follow up. Toxicity appears mild and notable for a low incidence of neutropenia, alopecia, and moderate peripheral neuropathy. This promising regimen avoids bleomycin, vinblastine, radiation and primary GCSF prophylaxis with resultant low toxicity and preserved high efficacy rates in patients with early favorable and early unfavorable non-bulky limited stage classical Hodgkin lymphoma. Follow up for this trial is ongoing. Figure. Figure. Disclosures Abramson: Merck: Consultancy; Seattle Genetics: Consultancy; Karyopharm: Consultancy; Verastem: Consultancy; Amgen: Consultancy; Humanigen: Consultancy; Juno Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Celgene: Consultancy. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board.

In an ECOG-ACRIN Cancer Research Group study (E1496), maintenance rituximab (MR) was reported to prolong progression-free survival (PFS) in comparison with observation (OBS) alone in patients with indolent lymphoma after induction chemotherapy. Here the long-term follow-up of the same patient cohort is presented.Patients with indolent lymphoma received induction chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP). Patients with stable disease or a better response were then randomized to weekly rituximab (375 mg/m(2) × 4 doses) every 6 months for 2 years (MR) or to OBS. The primary endpoint was PFS; the secondary endpoints were overall survival (OS), response rate, and toxicities.Of the 387 patients who initially received CVP induction, 158 were randomized to MR, and 153 were randomized to OBS. After a median follow-up of 11.5 years, patients on MR had longer median PFS (4.8 years) than patients on OBS (1.3 years; hazard ratio [HR], 0.49; P.0001). However, there was no difference in OS between MR and OBS (10-year OS, 67% vs 59%; median OS, 13.5 years vs not reached; HR, 0.91; P = .69). Other than MR, only minimal residual disease after induction therapy was significantly associated with PFS on multivariate analysis (HR, 0.71; P = .02). A low initial tumor burden, minimal residual disease, follicular histology, a low Follicular Lymphoma International Prognostic Index score, and female sex were associated with longer OS. There was no increase in the rate of second primary malignancies with MR vs OBS.With long-term follow-up, MR did not influence OS. The PFS benefit was maintained. MR should be considered optional for patients with indolent B-cell lymphoma. Cancer 2016;122:2996-3004. © 2016 American Cancer Society.

Evans syndrome (ES) is characterized by the simultaneous or sequential presence of multiple autoimmune cytopenias. It is often secondary to rheumatologic disorders or lymphoid malignancies, but has not previously been associated with babesiosis. Here we present two cases of severe cytopenias in asplenic patients precipitated by active babesiosis.The first patient had a history of Hodgkin's lymphoma in remission and autoimmune hemolytic anemia (AIHA) treated by splenectomy 12 years prior who presented with severe AIHA and thrombocytopenia after Babesia infection. The second patient had a history of ES requiring splenectomy, which relapsed after Babesia infection.The complex presentation and medical histories of both patients made the diagnosis challenging. Both patients' cytopenias responded to therapy, although the use of immunosuppressive agents in patients with active hematologic infections was challenging and required a multidisciplinary approach.These two cases illustrate the possibility of babesiosis to not only reactivate ES in asplenic patients, but also precipitate increased levels of immune deregulation, potentially provoking ES, a phenomenon not previously reported.

Anticancer treatment has recently shifted to include a broad range of antineoplastic therapies. Old agents are continuously being re-evaluated, and new mechanisms of treatment are rapidly being explored and developed. At the same time, the patient's perceived quality of life, adverse effects of therapy, time demands, and healthcare costs have become paramount in the treatment process. Lung cancer is the most common cause of cancer death in the USA, and because many of the patients are older or debilitated, these issues become all the more important. The oral administration of anticancer therapy offers both quality-of-life and healthcare cost advantages. Oral forms of 3 new cytotoxic agents and 2 novel oral therapies are discussed. Vinorelbine, a vinca alkaloid, has well documented activity in non-small cell lung cancer. Myelosuppression is dose limiting; neurotoxicity is rare. Satraplatin (JM-216), an oral platinum derivative, shows activity in lung cancer with a favourable adverse effect profile, with no neurotoxicity or nephrotoxicity. The oral topoisomerase I inhibitor topotecan may be ideal for obtaining long term low plasma drug concentrations, which appears to maximise efficacy. LGD-1069 is a retinoid X receptor agonist that modulates cell proliferation, and BAY-129566, a matrix metalloproteinase inhibitor, appears to interrupt both the processes of angiogenesis and metastasis. LGD-1069 and BAY-129566 are nontraditional anticancer agents which may be used in conjunction with chemotherapy, other modalities, or in prevention. These 5 agents will be discussed with particular reference to recent developments in the treatment of lung cancer.

Purpose To determine if alemtuzumab consolidation improves response rate and progression-free survival (PFS) after induction chemoimmunotherapy in previously untreated symptomatic patients with chronic lymphocytic leukemia. Patients and Methods Patients (n = 102) received fludarabine 25 mg/m2 intravenously days 1 to 5 and rituximab 50 mg/m2 day 1, 325 mg/m2 day 3, and 375 mg/m2 day 5 of cycle 1 and then 375 mg/m2 day 1 of cycles 2 to 6; fludarabine plus rituximab (FR) administration was repeated every 28 days for six cycles. Three months after completion of FR, patients with stable disease or better response received subcutaneous alemtuzumab 3 mg day 1, 10 mg day 3, and 30 mg day 5 and then 30 mg three times per week for 5 weeks. Results Overall response (OR), complete response (CR), and partial response (PR) rates were 90%, 29%, and 61% after FR, respectively; 15% of patients were minimal residual disease (MRD) negative. Of 102 patients, 58 received alemtuzumab; 28 (61%) of 46 patients achieving PR after FR attained CR after alemtuzumab. By intent to treat (n = 102), OR and CR rates were 90% and 57% after alemtuzumab, respectively; 42% of patients became MRD negative. With median follow-up of 36 months, median PFS was 36 months, 2-year PFS was 72%, and 2-year OS was 86%. In patients achieving CR after FR, alemtuzumab was associated with five deaths resulting from infection (viral and Listeria meningitis and Legionella, cytomegalovirus, and Pneumocystis pneumonias), which occurred up to 7 months after last therapy. The study was amended to exclude CR patients from receiving alemtuzumab. Conclusion Alemtuzumab consolidation improved CR and MRD-negative rates after FR induction but caused serious infections in patients who had already achieved CR after induction and did not improve 2-year PFS or survival.

A phase I/II trial evaluated early administration and dose escalation of interleukin (IL)-2 with granulocyte macrophage colony stimulating factor (GM-CSF) post-transplant. Following melphalan (200 mg/m(2)) and an autologous transplant, IL-2 was initiated (day 0) and continued for 4 weeks. GM-CSF (250 mcg/m(2)/day) began on day 5. Fifteen of 19 patients completed therapy. No treatment-related deaths occurred. IL-2 (1 x 10(6) IU/m(2)/day) was not tolerated in two of six patients due toor =grade 3 fatigue/diarrhea (n=1) or supraventricular tachycardia (n=1). The maximum tolerated dose of IL-2 was 6 x 10(5) IU/m(2)/day; this dose was well tolerated by 11 of 13 patients. Neutrophil and platelet engraftment occurred on day 13 (median; range 10-17 days) and day 13 (median; range 0-74 days), respectively. When compared to control patients, there was a marked increase in the number of CD3+ T cells (P=0.005), CD4+ T cells (P=0.01), CD8+ T cells (P=0.001) and CD4+CD25+Treg cells (P=0.015) post-transplant. Cytotoxicity directed against myeloma cells was markedly increased when compared to control patients (P=0.017). This unique trial design using early administration of IL-2 with GM-CSF during the period of lymphodepletion, demonstrated a marked increase in the number and function of early cytotoxic effector T cells, without suppression of engraftment.

Abstract 210 Background: Alemtuzumab (Campath-1H) is approved for the treatment of CLL. CALGB sought to determine whether alemtuzumab can improve the CR rate and eradicate MRD after induction chemoimmunotherapy by performing a phase II study administering FR followed by alemtuzumab consolidation to previously untreated, symptomatic CLL patients (pts). We previously reported preliminary toxicity data (Lin et al. ASH 2007) and now report final toxicity and response data. Methods: Pts received fludarabine 25 mg/m2 IV on days 1–5, and rituximab 50 mg/m2 IV on day 1, 325 mg/m2 on day 3, and 375 mg/m2 on day 5 of cycle 1 and then only on day 1 of cycles 2–6, repeated every 28 days for up to 6 cycles. Four months after the last fludarabine dose, pts with stable (SD) or responsive disease by NCI 96 criteria received SC alemtuzumab 3 mg on day 1, 10 mg on day 3, and 30 mg on day 5, and then thrice weekly thereafter for 6 weeks (18 total doses). Pts received standard Pneumocystis (PCP) and Varicella zoster virus prophylaxis and were monitored weekly by PCR for Cytomegalovirus (CMV) viremia. When unacceptable serious infectious toxicity was noted in pts who received alemtuzumab after achieving CR from FR induction, the study was amended so that only PR or SD pts received alemtuzumab after FR. Results: Median age of pts (n=102) was 61 years (range, 23–82), 74% were male, and 30% were Rai stage III/IV. FR was well tolerated; 93% of pts received at least 3 cycles, and 77% completed all 6 cycles. Overall, complete and partial response (OR, CR, PR) rates after FR induction were 90%, 29% and 61%, and 15% were MRD negative by flow cytometry. Fifty-eight pts received alemtuzumab, and 42 (72%) completed the planned 6 weeks of therapy. OR, CR, and PR rates after alemtuzumab (n=58) were 91%, 66% and 26%, and 50% were MRD negative. Twenty-eight of 45 pts (62%) in PR after FR who received alemtuzumab attained CR. Of 11 pts in CR after FR who received alemtuzumab, 5 were MRD negative prior to consolidation and 3 of the other 6 converted to MRD negative afterwards. By intent-to-treat for all patients enrolled, OR, CR, and MRD negativity were attained by 90%, 57% and 42% of pts. With a median follow up of 34 months, median progression free survival (PFS) was 37 months (95% CI, 33–43 months); PFS was 73% and overall survival (OS) 86% at 2 years. Two-year PFS (76% vs 70%, p=0.54) and OS (84% vs 88%, p=0.89) were similar for pts who did and did not receive alemtuzumab. Similarly, there were no differences in PFS or OS among the 30 pts in CR after FR whether or not they received alemtuzumab, although the numbers were small. Grade 3–4 neutropenia and thrombocytopenia were observed in 43% and 19% of pts during alemtuzumab therapy. Grade 3–4 non-hematologic toxicity was observed in 41% of pts, including 19% infections and 19% febrile neutropenia, during alemtuzumab therapy. As we previously reported, 5 pts in CR after FR who received alemtuzumab died from infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia), and one pt in PR after FR who received alemtuzumab died of Epstein-Barr (EBV) viremia without evidence of EBV lymphoma. These grade 5 toxicities occurred both during and for up to 7 months after alemtuzumab therapy. Conclusions: Alemtuzumab consolidation improved the CR and MRD negative rates after FR induction. However, alemtuzumab consolidation resulted in significant toxicity, particularly severe infections in pts who achieved a CR after FR induction. Longer follow up is needed to determine if the improved CR and MRD negative rates following alemtuzumab consolidation will eventually result in improved PFS or OS, especially among pts who achieved a PR after FR induction. Disclosures: Lin: GlaxoSmithkline: Consultancy, Employment; Genentech: Consultancy; Bayer: Consultancy. Off Label Use: Use of alemtuzumab as consolidation therapy. Byrd:Genentech: Consultancy, Research Funding. Link:Genentech: Consultancy. Rai:Genentech: Consultancy; Bayer: Consultancy.

Alemtuzumab (Campath-1H) is approved for the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL). Given the increasing role of chemoimmunotherapy in the treatment of CLL, the Cancer and Leukemia Group B initiated a phase II study administering FR followed by alemtuzumab for remission consolidation to previously untreated, symptomatic CLL patients (pts). Pts received fludarabine 25 mg/m2 IV on days 1–5; rituximab 50 mg/m2 IV on day 1, 325 mg/m2 IV on day 3, and 375 mg/m2 IV on day 5 of cycle 1, and 375 mg/m2 IV on day 1 of cycles 2–6; every 28 days for up to 6 cycles. Four months after the last dose of fludarabine, pts with stable or responsive disease by NCI 96 response criteria received consolidation therapy with SC alemtuzumab 3 mg on day 1, 10 mg on day 3, 30 mg on day 5, and 30 mg thrice weekly thereafter for 6 weeks. Pts received standard pneumocystis (PCP) and Varicella Zoster Virus prophylaxis and were monitored weekly for Cytomegalovirus (CMV) reactivation by PCR, antigen test, or hybrid capture. We report safety data on the first 51 pts who received alemtuzumab. Median age was 60 years (range, 23–82), and 75% were male. Of 34 pts who attained an NCI 96 partial response (PR) after FR induction, 9 (26%) experienced unacceptable toxicity to alemtuzumab, as defined prospectively by the study. Eight grade 3 toxicities (4 opportunistic infections, 3 CMV reactivation, 1 hemorrhagic cystitis), and 1 grade 5 EBV lymphoproliferative disorder were observed. In contrast, 17 pts had CR after FR induction and 8 (47%) had unacceptable toxicity. Complications included grade 3 infections in 3 pts (2 CMV, 1 cryptococcus) and 5 grade 5 infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia). These infections occurred both during therapy and for up to 16 months following therapy. Analysis of alemtuzumab pharmacokinetics and genomic tumor features is currently ongoing. Continuous real-time safety monitoring prompted a study amendment to prohibit further pts in CR after FR induction from receiving alemtuzumab consolidation. Accrual of new pts to the trial is complete. Only pts in PR or with stable disease after FR induction continue to receive alemtuzumab consolidation, with close monitoring for infectious and other toxicities. Detailed response and outcome data will be reported when all pts have completed therapy. We conclude that alemtuzumab cannot be safely administered as consolidation therapy to pts who achieve an NCI 96 CR following induction chemoimmunotherapy. The safety and feasibility of alemtuzumab consolidation for pts in PR after FR induction remains under study, and such therapy should not be pursued outside of a clinical trial due to concerns about serious infectious morbidity and mortality.

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.

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.

Autologous peripheral blood stem cell transplantation (APBSCT) is effective for the treatment of multiple myeloma (MM), however the majority of patients relapse. Recent evidence shows an improved outcome if absolute lymphocyte count is increased immediatedly following APBSCT in patients with hematologic malignancy. We designed a phase II trial evaluating a dose escalation of SQ IL-2 and standard dose GM-CSF post-transplant for myeloma patients. Patients (n=18) received melphalan 200mg/m2 with GM-CSF 250mg/m2/day beginning on day 5. IL-2 began on the day of transplant and continued 5 days per week for 4 weeks. Peripheral blood samples were obtained at baseline (pre-transplant) and every week for 4 weeks post-transplant and evaluated using flow cytometry for cell subsets using antibodies directed against CD3, CD4, CD8, CD25 and CD56. Control patients (n=11) consisted of MM patients who received melphalan 200mg/m2 with either G-CSF or GM-CSF without IL-2. IL-2 at a dose of 1 X 106IU/m2/d was not tolerated in 2 of 6 patients due to grade 4 fatique and diarrhea (n=1) and grade 4 supraventricular arrhythmia (n=1). A dose of 6 X 105 IU/m2/d was well tolerated by 12 patients. Level 3 or greater toxicities included nausea (n=5), diarrhea (n=3), anorexia (n=11), mucositis (n=9). Engraftment of neutrophils occurred on day 12 and platelets on day 18. The LOS was 21 days in IL-2 treated cohort and 18 days in control group. Absolute lymphocyte counts on days 10–15 were increased an average of 152% in the IL-2 cohort (range 25–390%) over the control group. At day 21, there was a marked increase in the number of CD3+CD8+ cytotoxic T cells (43 %, +/− 7.5%) , CD56 +NK cells ( 78.3 %, +/− 9.1), and CD8+CD56+ NKT cells (36.8 %, +/− 9.8%) compared to patients’ baseline levels. Cytotoxicity of Day #21 PBMNC in the IL-2 cohort was strikingly increased at 28.1% (18.5 – 29.2%) compared to 5.5 % (3.59 – 6.52%) at baseline when tested against a human myeloma cell line (RPMI 8226) using chromium release assays (E: T ratio = 100:1). These results demonstrate a tolerable regimen of immediate post-transplant immunotherapy with marked increase in the number and function of early cytotoxic effector cells. The enhanced immune recovery may translate into an improved outcome.