Dose Of Alemtuzumab Research Articles

Incidence and Severity of Leukopenia/Neutropenia in Kidney Transplant Recipients Following Single Dose Alemtuzumab Induction: A Prospective Review of 232 Patients.

Incidence and Severity of Leukopenia/Neutropenia in Kidney Transplant Recipients Following Single Dose Alemtuzumab Induction: A Prospective Review of 232 Patients.

P27. Alemtuzumab (anti-CD52 monoclonal antibody) as single-agent therapy in patients with relapsed/refractory chronic lymphocytic leukaemia (CLL) – a single region experience on consecutive patients

Alemtuzumab, a humanised CD52 monoclonal antibody, is routinely used as treatment for patients with refractory chronic lymphocytic leukaemia (CLL). Although alemtuzumab has been evaluated in numerous prospective clinical trials, little is known about its safety and efficacy in the routine clinical practice setting. Given that the haematology centers in the Stockholm area has gained substantial experience on alemtuzumab usage, starting already in the early 1990s, it would be of interest to compare our results obtained in routine health care with those from other reports including multicenter clinical trials. Records from 1301 patients with CLL from the Stockholm-Cancer-Registry (1991-2010) identified 56 patients treated with alemtuzumab in the relapsed or refractory setting. The median age was 69 years, 88% had advanced Rai stage with a median of 3 prior lines of therapy. One fourth had bulky lymphadenopathy and 73% were refractory to purine analogues. The median cumulative dose of alemtuzumab was 930 mg, being significantly higher (p=0.0277) for responders (1063 mg) compared to non-responders (643 mg). The median duration of therapy for responders was 12.4 weeks (range 7-32 weeks) and in all patients 11.6 weeks (range 1-51 weeks). The overall response rate (ORR) was 43%, with a response rate of 32.5%, 50% and 87.5% in the refractory, purine analogue relapsed and non-purine analogue relapsed group respectively. The differences in response rate was statistically significant (p=0.0104). A good performance status (PS) was associated with better response rate (ECOG 0-1 vs. ≥2) (p=0.0227). The median time to treatment failure (TTTF) was 7.8 months (range 0.4-55.4 months) being significantly longer for responders, 13.4 months (range 3.9-55.4 months) than for non-responders, 6.1 months (range 0.9-16.3 months) (p<0.0001). The median time to next therapy was 12.7 months (range 0.4-55.4 months). Major infections (defined as ≥ grade III) occurred in 36% of the patients. Cytomegalovirus reactivation was the most common opportunistic infection (75%) occurring in 9 patients. Median overall survival was 22.5 months (range 0.4-74.3 months). Responders had a significantly longer survival than non-responders, 44.2 and 16.3 months respectively (p=0.0006, log-rank test), although the difference when using the Landmark method was not significant. Predictive factors for longer survival was PS grade 0-1 (p<0.0001) and fewer previous treatment lines (1-3 vs. ≥4) (p=0.0038, log-rank test). Twelve patients were retreated with alemtuzumab at least once with an ORR of 50% and a TTTF of 7 months (range 0.5-13 months). In summary, a high cumulative dose/longer duration of therapy as well as relatively high response rates and long median survival was observed compared to what has been reported earlier in similar groups of patients having received alemtuzumab in trials or in routine health care in other areas. Optimal patient identification and management may result in avoidance of early discontinuation and possible better treatment outcomes.

Pancreas transplantation: The Wake Forest experience in the new millennium.

To investigate the Wake Forest experience with pancreas transplantation in the new millennium with attention to surgical techniques and immunosuppression. A monocentric, retrospective review of outcomes in simultaneous kidney-pancreas transplant (SKPT) and solitary pancreas transplant (SPT) recipients was performed. All patients underwent pancreas transplantation as intent-to-treat with portal venous and enteric exocrine drainage and received depleting antibody induction; maintenance therapy included tapered steroids or early steroid elimination with mycophenolate and tacrolimus. Recipient selection was based on clinical judgment whether or not the patient exhibited measureable levels of C-peptide. Over an 11.25 year period, 202 pancreas transplants were performed in 192 patients including 162 SKPTs and 40 SPTs. A total of 186 (92%) were primary and 16 (8%) pancreas retransplants; portal-enteric drainage was performed in 179 cases. A total of 39 pancreas transplants were performed in African American (AA) patients; of the 162 SKPTs, 30 were performed in patients with pretransplant C-peptide levels > 2.0 ng/mL. In addition, from 2005-2008, 46 SKPT patients were enrolled in a prospective study of single dose alemtuzumab vs 3-5 doses of rabbit anti-thymocyte globulin induction therapy. With a mean follow-up of 5.7 in SKPT vs 7.7 years in SPT recipients, overall patient (86% SKPT vs 87% SPT) and kidney (74% SKPT vs 80% SPT) graft survival rates as well as insulin-free rates (both 65%) were similar (P = NS). Although mortality rates were nearly identical in SKPT compared to SPT recipients, patterns and timing of death were different as no early mortality occurred in SPT recipients whereas the rates of mortality following SKPT were 4%, 9% and 12%, at 1-, 3- and 5-years follow-up, respectively (P < 0.05). The primary cause of graft loss in SKPT recipients was death with a functioning graft whereas the major cause of graft loss following SPT was acute and chronic rejection. The overall incidence of acute rejection was 29% in SKPT and 27.5% in SPT recipients (P = NS). Lower rates of acute rejection and major infection were evidenced in SKPT patients receiving alemtuzumab induction therapy. Comparable kidney and pancreas graft survival rates were observed in AA and non-AA recipients despite a higher prevalence of a "type 2 diabetes" phenotype in AA. Results comparable to those achieved in insulinopenic diabetics were found in the transplantation of type 2 diabetics with detectable C-peptide levels. In the new millennium, acceptable medium-term outcomes can be achieved in SKPT and SPTs as nearly 2/3rds of patients are insulin independent following pancreas transplantation.

Alemtuzumab in chronic lymphocytic leukemia: final results of a large observational multicenter study in mostly pretreated patients

This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced B-cell chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (B-PLL) to definitely describe the impact of this antibody in clinical routine use. Data were collected from 208 consecutive, mainly pretreated, patients with CLL (n = 202), and B-PLL (n = 6) who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) in various settings were assessed, and toxicities were documented. In these routine patients, a comparably low cumulative dose of alemtuzumab (median, 403 mg) was applied. In CLL, overall response rate was 32 %, and various pre-therapeutic parameters were predictive for inferior response, among them, the prior administration of ≥3 therapy lines (P < 0.001), refractoriness to fludarabine (P = 0.002), and bulky lymphadenopathy (P = 0.003). PFS and OS after start of alemtuzumab were 6.2 and 21.0 months, respectively. Bulky lymphadenopathy was the prominent risk factor for both inferior PFS (P < 0.001) and OS (P = 0.002). In B-PLL, four patients experienced a fatal outcome, whereas two patients had some benefit with alemtuzumab. The main adverse effects were CMV reactivation (20 %) and a broad spectrum of infections, which together were the main reasons for treatment interruption and/or premature termination. In conclusion, alemtuzumab administered even at low dose levels was effective but overall considerably toxic in routine CLL patients. We emphasize that alemtuzumab remains an important therapeutic option in subsets of CLL patients.

Outcomes of Allogeneic Hematopoietic Cell Transplantation In Aplastic Anemia Using Intermediate Dose Alemtuzumab Based-Conditioning

Unlike in hematologic malignancies, graft versus host disease (GVHD) has no therapeutic benefit in aplastic anemia (AA) and its prevention is highly desirable. Using conventional GVHD prophylaxis in AA, 30–40% of patients develop acute and chronic GVHD resulting in significant mortality and morbidity with long-term health issues and poor quality of life. Previous studies reported the favorable effect of alemtuzumab on acute GVHD in related and unrelated donor hematopoietic cell transplantation (HCT) for AA (Gupta et al, BBMT 2004; Gupta et al, BMT 2005). In these studies, a higher dose of alemtuzumab (75-100 mg) close to stem cell infusion was used. We subsequently designed a conditioning strategy using an intermediate dose of alemtuzumab (50-60 mg), and report our institutional experience at Princess Margaret Cancer Centre, Toronto, Canada using this strategy.Between January 2005 and June 2013, 40 patients underwent HCT for AA at our centre. The median age at HCT was 35 years (range 17-59). The etiology of AA was idiopathic in 70%. Fifteen (38%) were positive for paroxysmal nocturnal haemoglobinurea (PNH) clones and 2 patients had symptomatic hemolytic PNH prior to HCT. Upfront HCT was used in 17 (42%) patients, and 23 (58%) had failed one or two courses of ATG-based immunosuppressive therapy (IST). Donors were HLA-identical matched siblings in 28 (70%) and matched unrelated donors (MUD) in 12 (30%). As the preferred source of hematopoietic cells was bone marrow, 34 (85%) received BM grafts and 6 (15%) received peripheral blood grafts. Twenty four (60%) patients were CMV seropositive. Conditioning regimens included: High-dose cyclophosphamide (50 mg/kg x 4 days from days -5 to -2) with alemtuzumab 50 mg (10, 20, 20 mg on days -8, -7 and -6 respectively) in 9 (23%) patients; fludarabine (30 mg/m2 x 4 days from days -5 to -2) with low-dose cyclophosphamide (10 mg/kg x 4 days from days -5 to -2) and alemtuzumab 60 mg (30 mg x 2 days on days -7 and -6) in 28 (70%) patients. In 3 (7%) patients busulphan was used instead of low-dose cyclophosphamide because of symptomatic PNH or presence of monosomy 7. In the first 10 (25%) patients, alemtuzumab was used as an IV infusion; the subsequent 30 (75%) patients received subcutaneous alemtuzumab. Cyclosporine was also used for GVHD prophylaxis starting on day -1 and slowly tapered in the absence of GVHD at 6 months.The median follow up time of survivors was 3.6 years (range 0.2-7.9). The median neutrophil (≥0.5 x109/l) and platelet (≥20 x109/l) engraftment times were 18 days (range 11-112) and 12 (range 2-395) respectively. Four patients had graft failure (2 primary and 2 secondary). Two of these patients died and two are long-term survivors (one after second HCT and the other had autologous recovery). The cumulative incidences of acute and chronic GVHD were 27.7% (95% CI 13.5-41.8) and 21.3% (95% CI 7.9-34.7) respectively. No patients developed grade 3-4 acute GVHD or severe chronic GVHD (NIH criteria). Viral complications were seen frequently: CMV reactivation (79%); HSV (18%); VZV (25%) and BK hemorrhagic cystitis (8%). None developed CMV disease. Three patients developed an EBV-related lymphoproliferative disorder. All three patients were heavily treated with ≥2 courses of ATG- IST prior to HCT.The 3-year estimated overall survival was 85% (95% CI 74-97). The majority of patients had no significant long-term health issues. Of the 18 women of childbearing age (16-45 years), 6 patients conceived. An asymptomatic drop in FEV1 ≥20% was seen in only 4 of 21 patients who had survived >2 years. Two patients developed secondary malignancies (1 smouldering myeloma and 1 squamous cell carcinoma).In conclusion, this intermediate dose alemtuzemab based conditioning in AA is a simplified approach that results in excellent survival and has a favorable impact on GVHD, and long-term health issues. Nevertheless, close monitoring for viral complications such as CMV reactivation, and EBV monitoring particularly in patients who fail IST prior to HCT is important. Disclosures:Off Label Use: Alemtuzumab for GVHD prophylaxis in allogeneic hematopoietic cell transplantation for aplastic anemia.

Assessment Of The Endocrine Function Of Patients With Sickle Cell Disease After Allogeneic Hematopoietic Stem Cell Transplantation

Introduction While medical treatment of patients with sickle cell disease (SCD) has improved, hematopoietic stem cell transplantation (HSCT) remains the only curative treatment. Standard myeloablative conditioning regimens frequently lead to endocrine abnormalities of the hypothalamus-pituitary-gonadal, -thyroid and/or -adrenal axes. Methods Our group performed allogeneic HSCT in 14 female (ages 20-47 years) and 17 male (ages 16-64 years) patients with SCD using a non-myeloablative regimen: lower doses of total body irradiation (300 cGy instead of 1200 cGy), alemtuzumab (anti-CD52 monoclonal antibody), and sirolimus. Additionally, the gonads of male patients were shielded with two-sided clamshells to reduce radiation exposure. Endocrine function before, and at various time points up to several years after transplantation was analyzed. Results Thyroid function remained within the normal range at 12 months after HSCT, although free triiodothyronine (FT3) levels rose by 18.3% in six females and 19.9% in eight males [mean before/after HSCT: females: 269.4/318 pg/dL; males: 277.8/333.2 pg/dL]. Correspondingly, thyroid stimulating hormone (TSH) levels 12 months after transplantation were decreased by 24.1% in the six females and 33.7% in the eight males [mean before/after HSCT: females: 2/1.5 mcIU/mL; males: 2.5/1.7 mcIU/mL]. One of the female patient developed Grave's disease 36 months after HSCT, while a second female patient developed post-partum thyroiditis one month after giving birth, with persistent hypothyroidism at 48 months after HSCT. One male patient developed Hashimoto's thyroiditis 36 months after HSCT. The hypothalamus-pituitary-adrenal axes of both genders were not measurably impacted; nor was male gonadal function affected as evidenced by unaffected hormonal levels in most males at 12 months after HSCT [mean levels before/after HSCT: luteinizing hormone (LH) 6.5/6.5 U/L, follicle stimulating hormone (FSH) 9.4/6.5 U/L, total testosterone (TT) 359.9/358.3 ng/dL, calculated free testosterone (cFT) 7.6/7.6 ng/dL]. Three men have not yet reached the 12-months post transplant date. One found to have hypogonadotropic hypogonadism secondary to iron overload one year after HSCT (LH 5.4 U/L, FSH 4.2 U/L, cFT 1.9 ng/dL) and azoospermia, was successfully treated to father a child, while a second fathered two children without medical assistance. Among the remaining 14 males, the desire for fatherhood has not yet been expressed. In contrast, this non-myeloablative HSCT regimen affected the gonadal function of the females analyzed thus far. All women had SCD-related reduced ovarian function before HSCT. At twelve months after HSCT FSH levels were increased a mean of 6.2-fold (range: 2.4- to 15.2-fold) in eight females [mean before/after HSCT: 8.9/55.5 U/L], while LH levels rose a mean of 4.2-fold (range: 1.7- to 8.7-fold) in seven of the eight females [mean before/after HSCT: 11.5/35.9 U/L]. Mean estradiol levels fell at 12 months after HSCT by 62.8% in the eight women [mean before/after HSCT: 88.2/32.8 pg/mL] consistent with reduced/diminished ovarian function. Two females less than 12 months post transplant, have not yet had their gonadal function analyzed. Three natural pregnancies occurred in two women younger than 35 years, while two women over 40 years at the time of HSCT entered menopause thereafter. One woman with hypothalamic hypogonadism was not able to conceive. She underwent infertility evaluation, but did not pursue treatment for economic reasons. Nine women have not yet had a desire to conceive. Conclusion While this non-myeloablative regimen appears to impact the gonadal function of females, but not males, fertility is preserved in a subset of women. Further investigation of these patients is required to understand whether the immunosuppressive drugs administered in the setting of HSCT adversely affect ovarian function, and how to better preserve gonadal function of females undergoing non-myeloablative allogeneic HSCT. In addition, long-term follow-up of patients' thyroid functions beyond three years is advisable, as in our three patients, who developed thyroid dysfunction, the changes became evident not earlier than 36 months after HSCT. Disclosures: No relevant conflicts of interest to declare.

An Effective and Tolerable Chemoimmunotherapy Regimen For Relapsed/Refractory and Very-High Risk Chronic Lymphocytic Leukemia Combining Alemtuzumab With Pentostatin and Low Dose Rituximab

Patients with very-high risk (purine analogue refractory and TP53 defective) CLL have limited treatment options. In these patients alemtuzumab can be effective against CLL cells in the circulation and bone marrow, and in combination therapy with fludarabine can be active in patients with bulky disease, but these regimens have a high risk of serious infections. Addition of rituximab to alemtuzumab can also improve efficacy but has limited activity against bulky disease. We conducted a phase II clinical trial to determine the efficacy and toxicity of therapy with pentostatin, alemtuzumab, and low dose higher frequency rituximab (PAR) in patients with relapsed/refractory or progressive CLL with 17p13 deletion. The rituximab schedule was designed to decrease the loss of CD20 expression by circulating CLL cells. MethodsThis two-stage phase II trial study (NCT00669318) conducted at the Mayo Clinic Rochester and University of Iowa with IRB approval had an accrual goal of 38 evaluable patients. Eligibility required a diagnosis of progressive CLL by standard criteria and either previous treatment for CLL (<4 purine analogue regimens) or 17p13 deletion (17p13-). Exclusion criteria were organ failure, poor performance status (ECOG >3), infection with HIV, hepatitis B, hepatitis C, active autoimmune cytopenia, or alemtuzumab therapy within the past 2 months. Rituximab 20 mg/m2 IV M-W-F started on day 1, alemtuzumab started on day 3 with an escalation of 3-10-30 mg/d SQ and then 30 mg M-W-F from day 8, and pentostatin 2 mg/m2 IV every 2 weeks started on day 8. Peg-G-CSF or GM-CSF was used after each dose of pentostatin and patients received Pneumocystis and Varicella prophylaxis. CMV PCR assays were done weekly during treatment and viremia was treated with either valganciclovir or ganciclovir. Cycle 1 was 5 weeks and subsequent cycles were 4 weeks. At the end of cycle 2 patients with a clinical CR had a CT scan and a bone marrow study with immunohistochemical (IHC) staining for residual CLL cells, and therapy was stopped if there was no radiological or IHC evidence of residual CLL (stringent CR). Patients with residual disease received a 3rd cycle of therapy. ResultsForty-one patients were enrolled (July 2008 - February 2013) and all 39 who started therapy were evaluable for response: Median age 61 years (range 47-78), 30 (77%) males, 36 (92%) relapsed/refractory CLL (median prior regimens = 2, range 1-10), 3 (8%) previously untreated, 23 (59%) advanced stage (Rai III-IV), 16 (41%) intermediate stage (Rai I-II). Prognostic factors: FISH (hierarchical classification) 15 (38%) 17p13-, 6 (15%) 11q22-, 5 (13%) 12+, 3 (8%) no defects, 8 (21%) 13q14-, and 2 (5%) other abnormalities, IGHV analysis (n=38) 27 (71%) unmutated (<2%), ZAP-70 (n=37) 28 (76%) positive (>20%).Thirty (77%) patients completed planned therapy (28 had 3 cycles, 2 had 2 cycles with stringent CR). Nine patients received one (n=4) or two (n=5) cycles of therapy because of disease progression or complications. Grade 3-4 hematological adverse events (n=37) at least possibly related to treatment included neutropenia (n=22), thrombocytopenia (n=11), anemia (n=2) and hemolysis (n=2). Non-hematological adverse events (n=17) included infections/neutropenic fever (n=8), fatigue (n=3), and hemorrhage (n=2). CMV reactivation was detected and treated in 14 patients (grade 1-2). No patients died during treatment or from treatment related complications.The overall response rate was 56% (95% CI 40-72) with 4 (10%) CR, 7 (18%) CRi, 11 (28%) PR, 7 (18%) SD, and 10 (26%) PD. Four patients (3 CR and 1 CRi) had IHC negative bone marrow studies. Thirteen (33%) patients have died due to progressive CLL (n = 11), sepsis (n=1), and pneumonia (n=1). Median follow up for surviving patients is 23 months (range 3-55). Seven (18%) patients proceeding to RIC allogeneic transplant were censored for time to next treatment. Twenty-one (54%) patients required therapy for progressive CLL and 7 (18%) have required no further therapy. Median progression free survival was 7 months (95% CI: 5-16), time to next treatment 9 months (95% CI: 6-27) and median overall survival has not been reached. DiscussionPAR was effective and tolerable therapy for high-risk CLL. This study suggests that alemtuzumab can be used safely in combination with a purine analogue in a short-duration regimen. Disclosures:Zent:Genentech : Research Funding; Genzyme: Research Funding; Biothera: Research Funding; GlaxSmithKline: Research Funding; Novartis: Research Funding. Off Label Use: Pentostatin therapy for CLL, use of lower doses of rituximab.

Defining The Optimal Dose Of Alemtuzumab In Unrelated Donor Reduced Intensity Allografts: A UK Retrospective Study

Acute and chronic graft versus host disease (GVHD) represent major causes of morbidity and mortality following reduced intensity unrelated donor allografts, particularly in older patients. Alemtuzumab (AL, humanised anti-CD52 antibody) is highly effective at reducing the incidence of both forms of GVHD. There are a number of reported schedules used in this setting, with doses of between 50-100mg AL administered over 2-5 days. The timing of AL administration relative to stem cell return is also likely to have a significant impact on the depletion of donor T cells, but comparative data for unrelated donor transplants are lacking and the optimal dose and schedule remain unknown. In this three-centre retrospective study, we compared the post-transplant outcomes of patients receiving the same chemotherapeutic backbone of fludarabine 150mg/m2 and melphalan 140mg/m2 (flu-mel) along with the originally described AL regimen (100mg administered as 20mg/day, day -7 to -3, n=79), with those of patients receiving flu-mel and one of two alternative AL schedules: 60mg administered as 30mg/day, day -4 and -2, n=72; or 50mg administered as 10mg/day, day -7 to -3, n=107. In keeping with prior pharmacokinetic studies of de-escalating schedules in sibling donor cohorts, the day 1 serum AL levels in the 60mg cohort (median 4.7 mcg/ml, range 1.75-8.02 mcg/ml, n=14), did not differ significantly from historical data for the 100mg schedule. Donor lymphocyte infusions were given for mixed chimerism in all centres according to similar schedules starting at 6 months post transplantation. Median age at transplantation differed significantly between cohorts at 52, 45 and 56 years for the 100mg, 60mg and 50mg cohorts respectively (p = 0.005). Other statistically significant differences between cohorts were CMV status (p = 0.006) and disease indication (p = 0.0005); with AML patients constituting a majority in the 50mg cohort and lymphoproliferative disorder patients a majority in the 100mg cohort. No significant differences were detected between cohorts for HLA matching status (mismatched in 21/79 [27%], 12/72 [17%] and 33/107 [31%] respectively, p = 0.11), graft type (p = 0.06), or disease status at transplantation (p = 0.09). The incidences of acute grade II-IV GVHD were 35%, 32%, and 38% (p = 0.6) for the 100mg, 60mg and 50mg cohorts respectively, whilst those for grade III-IV GVHD were 4%, 6%, and 15% (p = 0.02). The corresponding incidences of chronic GVHD at 2 years were 29%, 28% and 39% respectively (p = 0.38). A trend towards a higher incidence of chronic GVHD in the 50mg cohort was confirmed by comparison with the combined data for the other 2 cohorts (29% vs 39%, p = 0.17). In the high-risk CMV cohort (seropositive recipient), reactivation requiring anti-viral therapy occurred in 97%, 77% and 76% respectively (p = 0.02). The incidences of full donor T-cell chimerism (&gt;97% donor according to assay sensitivity) at day 100 were 56%, 29% and 44% respectively (p = 0.02). There were no significant differences with respect to non-relapse-related mortality at two years post-transplant (28%, 27% and 29% respectively, p = 0.57). Although univariate analyses of relapse rates and overall survival were confounded by the differences in patient characteristics between cohorts, no significant differences were observed (relapse rate at 3 years 20%, 20%, and 26%, p = 0.39; overall survival at 3 years 59%, 64% and 37%, p = 0.05). In conclusion, this study represents the first attempt to define an optimal dosing schedule for AL in unrelated donor allograft recipients, and suggests that significant reduction in AL dose is achievable for patients receiving flu-mel conditioning with unrelated donor grafts. There was evidence of more acute grade III-IV GVHD with the 10mg/day x5 schedule, and a trend towards a higher incidence of chronic GVHD, whilst the 30mg/day x2 schedule delivered similar results to the 20mg/day x5 schedule, perhaps in keeping with the comparable day 1 serum AL levels. Lower alemtuzumab doses were associated with a modest reduction in the risk of CMV reactivation in high-risk patients. Whilst the usual caveats associated with retrospective cross-institutional comparative studies apply, the data suggest that reduction to 30mg/day x2 is not associated with any significant detrimental impact and may be preferable on economic grounds. Disclosures: No relevant conflicts of interest to declare.

Bendamustine plus alemtuzumab is safe and feasible treatment for fludarabine refractory chronic lymphocytic leukaemia (CLL)

Bendamustine plus alemtuzumab is safe and feasible treatment for fludarabine refractory chronic lymphocytic leukaemia (<scp>CLL</scp>)

An Intermediate Alemtuzumab Schedule Reduces the Incidence of Mixed Chimerism Following Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Hemophagocytic Lymphohistiocytosis

Reduced-intensity conditioning (RIC) improves the outcomes of hematopoietic cell transplantation (HCT) in patients with hemophagocytic lymphohistiocytosis (HLH). Proximal (ie, close to graft infusion) dosing of alemtuzumab is associated with a high incidence of mixed chimerism, whereas distal (ie, distant from graft infusion) dosing is associated with less mixed chimerism but more acute graft-versus-host disease (GVHD). The alemtuzumab dose per kilogram of body weight also influences these outcomes. We hypothesized that an intermediate alemtuzumab dosing schedule would reduce mixed chimerism and maintain a low incidence of acute GVHD. In this study, 24 consecutive HCTs were performed in patients with HLH or a related disorder using a novel intermediate alemtuzumab schedule of 1 mg/kg starting on day -14. The cumulative incidences (CIs) of mixed chimerism, upfront acute GVHD grades II-IV, and receipt of additional hematopoietic cell products after HCT were compared in patients treated with a distal alemtuzumab schedule (n = 15) and those treated with a proximal alemtuzumab schedule (n = 33). All patients received fludarabine and melphalan. The CI of mixed chimerism was 31% in the intermediate group, 72% in the proximal group (P < .01), and 75% in the distal group patients who received ≥2 mg/kg alemtuzumab (P = .03). The CI of acute GVHD grades II-IV before the development of mixed chimerism was 4% in the intermediate group, 0% in the proximal group, and 13% in the distal group (P = .04, proximal versus distal). The 1-year CI of administration of additional hematopoietic cell products for mixed chimerism (donor lymphocyte infusion ± hematopoietic stem cell boost ± repeat HCT) was 14% in the intermediate group, 53% in the proximal group (P = .01), and 38% in the distal ≥2 mg/kg alemtuzumab group (P = .02). Our findings indicate that intermediate RIC reduces the incidence of mixed chimerism, is associated with a low incidence of upfront acute GVHD, and decreases the need for additional hematopoietic cell products after HCT.

Lowering the alemtuzumab dose in reduced intensity conditioning allogeneic hematopoietic cell transplantation is associated with a favorable early intense natural killer cell recovery

Background aimsThe anti-CD52 monoclonal antibody alemtuzumab is employed in allogeneic hematopoietic cell transplantation (alloHCT) for the prevention of graft-versus-host disease (GVHD). However, its optimal dosing in this setting has not been determined yet. We compared three different alemtuzumab dose levels in reduced intensity conditioning (RIC) alloHCT with respect to lymphocyte recovery and outcome. MethodsIn 127 consecutive patients with predominantly advanced stage hematologic malignancies, a first alloHCT after RIC was performed, applying a fludarabine-based protocol (in 93% FBM: fludarabine, bis-chloroethyl-nitrosourea [BCNU], and melphalan). For GVHD prophylaxis, cyclosporine and alemtuzumab at three different dose levels (40 mg, 20 mg, 10 mg) were administered. Recovery of the peripheral blood (PB) lymphocyte sub-populations and clinical outcome were determined with regard to the alemtuzumab dose. ResultsNatural killer (NK) cell concentrations in PB around day +30 correlated inversely with the alemtuzumab dose, whereas other PB lymphocyte subtypes remained essentially unaffected by dosing of alemtuzumab. Lower alemtuzumab doses were associated with a tendency toward improved overall survival mainly during the early post-transplantation months. With regard to the PB NK cell concentration around day +30, “early intense NK cell reconstituters” tended to show an overall survival benefit. ConclusionsAn alemtuzumab dose reduction to only 10–20 mg provides sufficient GVHD prophylaxis and supports improved NK cell regeneration early after alloHCT in PB (“NK cell saving effect”), which may have a positive effect on overall survival.

A phase I study of escalated dose subcutaneous alemtuzumab given weekly with rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma

This study assessed the safety and preliminary efficacy of escalated dose subcutaneous alemtuzumab in combination with rituximab in chronic lymphocytic leukemia. Twenty-eight patients with relapsed refractory chronic lymphocytic leukemia were treated on four dosing cohorts of weekly rituximab at 375 mg/m(2) and alemtuzumab doses that started at 30 mg three times per week and escalated to weekly dosing over four weeks, culminating with 90 mg weekly. One dose limiting toxicity of a rituximab infusion reaction was seen in cohort 2, but the regimen was otherwise well tolerated without evidence of differential toxicity by cohort. The overall response rate by National Cancer Institute-Working Group criteria was 61%, and the rate of complete bone marrow response was 43%, most of whom were negative for minimal residual disease. The addition of CT scan evaluation per International Workshop on Chronic Lymphocytic Leukemia 2008 criteria reduced the overall response rate to 14%. Median overall survival was 35 months, with 12 patients able to proceed to stem cell transplantation. Pharmacokinetic studies showed that chronic lymphocytic leukemia involving more than 80% of the bone marrow at study start was associated with lower trough concentrations of alemtuzumab and rituximab, and that higher trough serum concentrations of alemtuzumab were associated with complete bone marrow clearance. We conclude that escalated subcutaneous doses of alemtuzumab given weekly are well tolerated and result in excellent bone marrow clearance of chronic lymphocytic leukemia, helping patients to proceed to stem cell transplantation. This study is registered at ClinicalTrials.gov (Identifier:00330252).

2117 PEDIATRIC STEROID-FREE DECEASED-DONOR RENAL TRANSPLANTATION WITH ALEMTUZUMAB INDUCTION: A SEVEN-YEAR EXPERIENCE

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation, Renal Vascular Surgery1 Apr 20132117 PEDIATRIC STEROID-FREE DECEASED-DONOR RENAL TRANSPLANTATION WITH ALEMTUZUMAB INDUCTION: A SEVEN-YEAR EXPERIENCE Jonathan J. Melquist, Heather N. DiCarlo, Deirdre Connolly, Joseph Caputo, Richard Fine, Katarina Supe-Markovina, Wayne C. Waltzer, and Frank S. Darras Jonathan J. MelquistJonathan J. Melquist Stony Brook, NY More articles by this author , Heather N. DiCarloHeather N. DiCarlo Baltimore, MD More articles by this author , Deirdre ConnollyDeirdre Connolly Stony Brook, NY More articles by this author , Joseph CaputoJoseph Caputo Stony Brook, NY More articles by this author , Richard FineRichard Fine Stony Brook, NY More articles by this author , Katarina Supe-MarkovinaKatarina Supe-Markovina Stony Brook, NY More articles by this author , Wayne C. WaltzerWayne C. Waltzer Stony Brook, NY More articles by this author , and Frank S. DarrasFrank S. Darras Stony Brook, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2026AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Alemtuzumab (Campath-1H, C1H) is a monoclonal antibody targeting CD52 receptors on B- and T-lymphocytes and is an effective induction agent in renal transplantation. We report a seven-year experience using C1H induction and steroid-free protocol in the pediatric population as safe and effective. METHODS Between 2006 and 2012, 21 pediatric deceased-donor renal transplants were performed at a single academic center. Mean recipient age was 14.3 years (range 4 - 18). Six of the 21 recipients were African-American, 8 were Hispanic, 7 were Caucasian, 14 were male, and 3 were re-transplants. All 21 pediatric recipients received a single intraoperative dose of alemtuzumab (0.6 mg/kg, range 10-30 mg), 3 doses of IV methylprednisolone, tacrolimus (TAC), and low-dose mycophenolate mofetil (MMF). Immunosuppression was maintained using TAC and MMF. RESULTS The average follow-up period was 32 months. All patients had immediate graft function. Graft survival was 95% and patient survival was 100%. Mean 12- and 36-month eGFR were 60.3±28.9 and 56.4±14.4 mL/min/1.73m2, respectively. Two patients developed acute T-cell mediated rejection on average 10.5 months from transplantation (See Figure). One was treated successfully. The other one had a transplant nephrectomy at 20 months for graft failure believed to be secondary to the patient's persistent non-compliance with the immunosuppression regimen. No pediatric recipients developed cytomegalovirus (CMV) infection, post-transplant lymphoproliferative disease (PTLD) or Polyoma BK viral nephropathy. No cases of post-transplant diabetes mellitus (PTDM) or hyperlipidemia have been seen in this group. All 21 patients stayed on TAC and low-dose MMF throughout their post-transplant course. CONCLUSIONS Steroid-free immunosuppression with single dose C1H induction provides adequate and safe immunosuppression in pediatric deceased-donor renal transplant recipients receiving TAC and low-dose MMF maintenance therapy. These results compare favorably with our adult renal transplant experience. The authors plan to continue their current steroid-free protocol in existing and future patients. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e867-e868 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jonathan J. Melquist Stony Brook, NY More articles by this author Heather N. DiCarlo Baltimore, MD More articles by this author Deirdre Connolly Stony Brook, NY More articles by this author Joseph Caputo Stony Brook, NY More articles by this author Richard Fine Stony Brook, NY More articles by this author Katarina Supe-Markovina Stony Brook, NY More articles by this author Wayne C. Waltzer Stony Brook, NY More articles by this author Frank S. Darras Stony Brook, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Low-dose alemtuzumab vs. standard policy for prevention of graft-versus-host disease in unrelated and related allogeneic stem cell transplantation—a matched pair analysis

Antibody-mediated in vivo T cell depletion is common prior to unrelated (URD) or mismatched allogeneic stem cell transplantation (alloSCT) and optional in HLA-identical sibling (FAM) alloSCT. While anti-thymocyte globulin (ATG) is the current standard, alemtuzumab is an alternative. The optimal dose of alemtuzumab has not been defined. This retrospective analysis compares low-dose alemtuzumab with ATG in URD alloSCT and with no antibody in FAM alloSCT. Twenty-eight patients treated with alemtuzumab (10mg; HLA mismatch, 20mg) were matched to 28 patients who have either received ATG (URD) or no antibody (noAB) according to disease, disease stage, age, transplant type and risk state. Both groups were compared for engraftment, outcome, disease-free (DFS) and overall survival (OS), graft-versus-host disease (GvHD), freedom from GvHD (ffGvHD) and transplant-related mortality (TRM). No significant differences were found between the groups for leukocyte engraftment, GvHD, ffGvHD, TRM, DFS and OS. There was a trend for reduction of cGvHD by alemtuzumab (p = 0.05). A transplant-type stratified subanalysis consolidated equivalency of alemtuzumab and ATG in URD-SCT and indicates possible superiority of low-dose alemtuzumab compared to noAB in FAM-SCT. Low-dose alemtuzumab, as part of conditioning regimen prior to alloSCT, is safe and comparable to standard ATG. Prospective trials, particularly comparing alemtuzumab vs. noAB in FAM alloSCT, should be conducted.

In vivo T‐cell depletion with alemtuzumab in allogeneic hematopoietic stem cell transplantation: Combined results of two studies on aplastic anemia and HLA‐mismatched haploidentical transplantation

We evaluated the efficacy of in vivo T-cell depletion with alemtuzumab in two prospective studies according to the International Conference on Harmonisation (ICH)-Good Clinical Practice (ICH-GCP) guidelines; one was for patients with aplastic anemia (AA study) and the other was for patients who were undergoing hematopoietic stem cell transplantation (HSCT) from a 2- or 3-antigen-mismatched haploidentical donor (MM study). The final dose of alemtuzumab in these studies was 0.16 mg/kg/day for 6 days. At this dose, all of the 12 and 11 patients in the AA and MM studies, respectively, achieved initial engraftment and the incidences of Grade II-IV acute graft-versus-host disease (GVHD) were 0% and 18%. While cytomegalovirus (CMV) frequently reactivated, none of the patients developed fatal CMV disease. Transplantation-related mortality within 1 year after HSCT was observed in only two and one patients, respectively. The numbers of CD4+ and CD8+ T-cells and T-cell receptor rearrangement excision circles remained low within 1 year after HSCT. These findings suggest that the use of alemtuzumab at this dose in a conditioning regimen enables safe allogeneic HSCT even from a 2- or 3-antigen-mismatched donor. However, the use of a lower dose of alemtuzumab should be explored in future studies to accelerate immune recovery after HSCT.

Alemtuzumab induction in pediatric kidney transplantation

Recipient parenchymal lymphatic cells are crucial for direct and indirect pathways of allorecognition. We proposed that alemtuzumab, being infused several weeks pretransplant could eradicate peripheral lymphatic cells and promote donor-specific tolerance. We present here a single center, retrospective review of 101 consecutive living-donor kidney transplantations to pediatric patients aged from seven month to 18 yr, performed between September 2006 and April 2010. Immunosupression protocol included two 30 mg doses of alemtuzumab: first given 12–29 d prior to transplantation and second at the time of transplantation. Maintenance immunosupression was based on combination of low dose and wide range CNI and mycophenolate. Patients were followed for 3.8 ± 1.4 yr and protocol biopsies were taken one month, one, and three yr post transplant. The Kaplan–Meier graft and patient survival was 96% and 97% for one yr, 89% and 93% for three yr. Biopsy proven acute rejection developed in 26% patients at one yr and in 35% at two yr, no rejections occurred beyond two yr. We conclude that alemtuzumab pretreatment prior to living related donor kidney transplantation allows to reach satisfactory middle-term results in pediatric patients with wide range and low CNI concentrations.

Phase I Study of Alemtuzumab for Therapy of Steroid-Refractory Chronic Graft-versus-Host Disease

Steroid-refractory chronic graft-versus-host disease (cGVHD) carries a poor prognosis with no agreed upon algorithm for treatment. Because both B and T cells contribute to the pathophysiology of cGVHD, we conducted a phase I study in subjects with steroid-refractory cGVHD using the anti-CD52 antibody alemtuzumab to transiently deplete most mononuclear subsets. Three regimens were investigated in a 3+3 dose-escalation design: 3 mg × 6 (dose level 1), 3 mg × 1, then 10 mg × 5 (dose level 2) and 3 mg × 1, 10 mg × 1, then 30 mg × 4 (dose level 3) administered over 4 weeks. The maximum tolerated dose of alemtuzumab was dose level 2. Thirteen patients were assessable for toxicities, which were primarily infectious and hematologic. Rates of infectious complications in the first 12 weeks were 0% at dose level 1 (n = 3), 50% at dose level 2 (1 death, n = 6), and 75% at dose level 3 (2 deaths, n = 4). Of 10 patients assessable for response, 7 (70%) responded at 12 weeks, with a 30% complete response rate. Four subjects reduced steroid dose or discontinued an immunosuppressant at 12 weeks. The median decrease in steroid dose at 1 year was 61.6%. Infectious complications occurred predominantly in the first 3 months after therapy, but full B and T cell recovery took well over 12 months. Immunophenotypic profiling revealed early recovery by natural killer cells and relative sparing of CD4+ and CD8+ central memory T cell subsets. Our study indicates that therapy with alemtuzumab for steroid-refractory cGVHD is tolerable with close attention to dosing and may be active in subjects who have failed multiple therapies. The pattern of lymphocyte recovery after alemtuzumab will inform the biology and future therapy of cGVHD. The use of alemtuzumab in the context of therapy for cGVHD deserves study in larger phase II trials.

Engraftment Kinetics After Alimtuzumab-Based Allogeneic Stem Cell Transplant (SCT): Full Donor T-Cell Chimerism Did Not Predict for Acute Graft Versus Host Disease (GVHD) or CMV Reactivation

Abstract 4162 Background:Graft versus host disease (GVHD) remains the leading cause of the treatment failures following an otherwise successful allogeneic Stem Cell Transplant. Alemtuzumab – based prophylactic regimens is evolving as an important option for prevention of this devastating complication. Multiple phase II studies suggested that patients who received Alemtuzumab –containing GHVD prophylactic regimens tends to have less acute GVHD though the utility is limited by increased incidence of mixed chimerism often requiring donor lymphocytes infusion and cytomegalovirus reactivation. Hypothesis:We hypothesize that if we could identify an optimal dose of Alemtuzumab; we could maintain the benefit of lowering the incidence of GVHD and also minimize mixed chimerism and CMV reactivation following the transplant. Method:To test our hypothesis, we conducted a pilot study utilizing the combination of Alemtuzumab (20 Related Donor: 30 mg on Day -1; 10 Unrelated donor: 30 mg daily on Day -2 & Day -1) and cyclosporine as GVHD prophylaxis. Between 5/11 and 5/12, 28 pts were included in the study. There were 15 females and 13 males. The diagnosis included 16 AML, 3 NHL, 2 MDS, 1 CML, 1 CLL, 1 ALL, 1 HD, 1 PLL, 1 MPD and 1 MM. Conditioning regimens consisted of Fludarabine/Melphalan in 20, Fludarabine/Busulfan in 5, TBI/Cy in 2 and Fludarabine/Clofarabine in 1. Upon achievement of engraftment, we monitor CMV by PCR weekly and engraftment by Short tandem repeat (STR) monthly with T-cell and Myeloid subsets analysis. Results:26/28 pts achieved neutrophils engraftment except 1 died shortly after SCT from heart failure and 1 experienced primary graft failure with day 30 STR showing only 3% donor T-cell chimerism. On Day 30 post-SCT, all evaluable pts had predominately donor T-cell (median 99%; 19/27 (70%) ≥ 99%; range 82 to > 99%) and Myeloid Chimerism (24/26 (92%) ≥ 99% except one pt who developed rapidly progressive leukemia phase PTLC after transplant. 25 pts (89%) survived beyond Day 90 post-SCT and have engraftment data available for analysis. On Day 90 analysis, while most pts maintain predominant donor myeloid chimerism (> 95%; median 99%); only 10/25 (40%) had maintained 99% donor T-cell chimerism. In addition, 76% pts had their T-cell donor chimerism worsened by Day 90 when compared with Day 30 analysis (9 pts dropped below 80%; range 8–75%). On the other hand, no pt developed secondary graft failure. 5 pts (17%) developed acute GVHD with only 1 (4%) Grade IV aGVHD. 8 pts (29%) developed CMV reactivation within day 100 post-SCT. Full donor T-cell chimerism did not predict for GVHD or CMV reactivation. With longer follow up, some pts’ have donor T-Cell chimerism increased with tapering of immunosuppressive therapy with or without GVHD or after receiving DLI. Conclusion:1. Our preliminary data suggested that using a lower dose of Alemtuzumab (30 mg for RD and 60 mg for MUD) as GVHD prophylaxis is effective to prevent GVHD though still associated with high incidence of CMV reactivation. 2. Most pts achieve predominant Donor T cell chimerism on day 30 though many worsen on subsequent follow-up. 3. Although it appears that there's no impact on durability of engraftment, longer follow-up is required to determine the impact on relapse, chronic GVHD and survival. Disclosures:Fung:Genzyme: Honoraria. Off Label Use: Alemtuzumab for GVHD prophylaxis.

Hemophagocytic Lymphohistiocytosis: Truly On the Rise or Simply On the Radar?.

AbstractAbstract 2151 BackgroundHemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disorder of the immune system that appears to be increasing in incidence. HLH induces a hyperinflammatory state that mimics sepsis with stimulated and unregulated proliferation of T lymphocytes, macrophages, and cytokines. While first described in infants and children, the incidence now appears to be increasing in adults, as evident by the increase of case series and reports currently in the literature. Given the rarity of HLH, there is little clinical data to guide treatment decisions but the disease is uniformly fatal without treatment. Our study aims to define the incidence of HLH at our institution, characterize its course, and identify strategies to improve outcomes. MethodsIn this single-center retrospective case series, following IRB approval, all documented cases of HLH diagnosed or treated at Beth Israel Deaconess Medical Center between 1997 and 2011 were analyzed. Cases were identified by a query of all inpatient and outpatient visits using ICD-9 billing code 288.4, hematopathology record review and review of cases from the hematologic malignancy clinical service. Forty-two patients were identified and 18 were included in the final analysis. Twenty-three were excluded due to alternative diagnoses and 1 was excluded due to the date of diagnosis being outside the study time period. Vital statistics, demographics and clinical data were collected on all eligible patients. ResultsThe key findings from our case series are highlighted below in Table 1.Table 1Patient characteristicsN=18Age at diagnosis (mean)60 years (range 22-77)Gender13/18 Male (72%)Ethnicity13/18 White (72%)2/18 Black (11%)1/18 Hispanic (6%)2/18 Asian (11%)Vital status14/18 expired (78%)Rural vs. urban16/18 rural (89%)Year of diagnosis2005 – 1 (6%)2007 – 3 (17%)2008 – 2 (11%)2009 – 7 (39%)2010 – 2 (11%)2011 – 3 (17%)Primary or secondary HLH9/18 primary (50%)Met HLH criteria7/18 (39%)Required pressors6/18 (33%)Required ICU level care11/18 (61%)Received steroids18/18 (100%)Received etoposide9/18 (50%)Received cyclosporine13/18 (72%)Achieved remission6/18 (33%)Received additional treatment7/18 (41%) received additional chemotherapy6/18 (33%) received additional immune modulators DiscussionOur study illustrates several interesting points. First, there were no identifiable cases of HLH at our institution before 2005 but multiple cases have been diagnosed annually since 2007. This rise may represent an increase in diagnosis due to greater awareness of the disease or may point to a new environmental trigger or exposure resulting in a true increase in incidence. Interestingly, 89% of patients diagnosed with HLH in our series were from rural areas with a spike in incidence in 2009, the year of the H1N1 pandemic. Information about patients' influenza status was not available for this analysis but raises the question if this strain of influenza may have triggered a rise in incidence in HLH at our institution. The second observation is that only 39% of our patients met the suggested clinical criteria for a diagnosis of HLH, yet all were clinically managed as HLH (Henter et al, Pediatr Blood Cancer 2007). This highlights the difficulty in diagnosing patients as several of the diagnostic labs are not easy to obtain. Our last observation is that this remains a highly lethal disease with a mortality of 78% in our population. In following the HLH-2004 treatment protocol (Henter et al, Pediatr Blood Cancer 2007), 100% of patients received steroids but only 72% received an immunosuppressant and only half received etoposide. One-third of treated patients attained remission but there were only four survivors in this case series. Three of the survivors had secondary HLH due to lymphoma, rheumatoid arthiritis (RA) and CMV infection. Only one survivor had primary HLH. The patient with RA was treated with the HLH-2004 protocol initially but was then switched to alemtuzumab due to persistent disease. He remains in remission 8 months after his last dose of alemtuzumab. In conclusion, there has been an increase in HLH incidence at our institution of unclear etiology. The majority of patients die of HLH despite efforts to use the HLH-2004 protocol, and many patients are unable to receive the full protocol. Further investigation is needed to determine the etiology of its increased incidence and to develop better treatment strategies in the adult population. Disclosures:Off Label Use: Alemtuzumab was used as a second-line therapy for a patient with secondary HLH in an off-label fashion.

First Interim Efficacy and Safety Analysis of an International Phase III Randomized Trial in Newly Diagnosed Systemic Peripheral T-Cell Lymphoma Treated with Chemotherapy with or without Alemtuzumab and Consolidated by High Dose Therapy

AbstractAbstract 57 BackgroundThe ACT trial (ACT-1, younger patients aged 18–60 yrs and ACT-2, elderly patients aged >60 yrs) is the first international randomized phase III trial in newly diagnosed primary systemic peripheral T-cell lymphoma (PTCL). It tests, in both younger and elderly patients, the efficacy of the addition of alemtuzumab (ALZ) to 6 courses of bi-weekly CHOP followed, only in younger patients (ACT-1), by high-dose therapy with autologous stem cell rescue. A dose reduction amendment tapering the cumulative ALZ dose from 360 mg (30 mg on days 1 and 2 of CHOP courses 1–6) to 120 mg (30 mg on day 1 of CHOP courses 1–4), respectively, was introduced early on due to two cases of systemic fungal infection (Blood 2011,118;4110). To date, the trial has accrued a total of 186 patients (ACT-1 n=98; ACT-2 n=88). AimHere, we present the results from the first interim efficacy and safety analysis of the ACT-1 trial based on the first 68 randomized patients. ResultsOf the 68 patients, 63 had a complete set of treatment data. The median follow-up was 15 months (range 0.5–42 months). Thirty-two patients belonged to the experimental arm (exp) and 31 to the standard arm (std). Of the 32 patients treated according to exp, 4 received the higher dose of ALZ and 28 the lower. Treatment arms were well balanced with regard to main prognostic features such as age (std: median 53 yrs, range 21–60 yrs; exp: median 50 yrs, range 22–64 yrs; p=0.705), IPI subgroups (std: low 10%, low-intermediate 51%, intermediate-high 29%, high 10%; exp: low 12%, low-intermediate 44%, intermediate-high 19%, high 25%; p=0.392), advanced clinical stage (std: stage III-IV 94%; exp: 97%; p=0.613), performance status ECOG>1 (std: 23%; exp: 28%; p=0.613), elevated LDH (std: 68%; exp: 69%; p=0.932), presence of B-symptoms (std: 68%; exp: 75%; p=0.524), bulky disease (std: 13%; exp: 13%; p=1.0) and bone marrow involvement (std: 39%; exp: 31%; p=0.535). Histological subtypes were also similarly distributed among both treatment arms (std: PTCL-NOS 55%, AILT 23%, other 22%; exp: PTCL-NOS 56%, AILT 28%, other 16%). No cases of anaplastic large cell PTCL (regardless of ALK-protein status) were included. Neither of the treatment cohorts showed significant treatment delay. The median duration of chemotherapy (calculated for 5 bi-weekly cycles of an expected cumulative duration of 70 days) for non-ALZ vs. ALZ-treated patients was 73 vs. 81 days, respectively. No suspected unexpected serious adverse reactions (SUSARs) were reported. Grade 4 leucopenia was more frequent in ALZ-treated patients (std: 24%, exp: 69%; p=0,001), whereas grade 3–4 anemia and grade 3–4 thrombocytopenia were not significantly different between treatment arms (anemia, std: 19%, exp: 31%; p=0,278; thrombocytopenia, std: 20%, exp: 12%, p=0,682). Non-hematological toxicity unrelated to infectious complications was mild and had a similar frequency in both arms. The number of serious adverse events (SAEs) per patient was 0.86 for patients treated at post-amendment ALZ dose levels, representing a significant reduction compared to the pre-amendment value (3.25), and 0.46 for patients treated in the control arm (p=0.002). The frequency of bacterial and fungal infections (grade ≥3) was similar in both treatment arms. ALZ treated patients had more viral events (9/32; 28% vs. 3/31; 10%), mainly (6 out of 9) consisting of asymptomatic cytomegalovirus reactivations. The overall (non-arm specific) 1-year event-free survival (primary end-point), progression-free survival and overall survival were 55% (95% CI: 42%-67%), 54% (95% CI: 42%-67%) and 78% (95% CI: 67%-88%), respectively. ConclusionThe safety profile of the current standard and experimental treatment schedules, as well as the interim outcome results, support a continuation of the trial. A final analysis will be performed in Q2 2015. Disclosures:Jantunen:Genzyme: Has participated in EU Leadership meeting organized by Genzyme as well as Medical Advisory Board meeting organized by Genzyme Other, Honoraria.