landmarks Lymphoma STUDY SUMMARY: Immediate use of rituximab may change standard of care

Lymphoma Improving Time to Initiation of New Therapy Douglas Stewart, MD, FRCPC, Chief, Division of Hematology & Hematologic Malignancies, University of Calgary; Provincial Leader, Hematology Tumour Team, Alberta Health Services (AHS) Cancer Care. STUDY SUMMARY: Immediate use of rituximab may change standard of care Ardeshna KM, Qian W, Smith P et al. An Intergroup randomised trial of rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky follicular lymphoma (grades 1, 2 and 3a). A preliminary analysis. Blood (ASH Annual Meeting Abstracts). Nov 2010;116: Abstract 6. This study compared a watchful waiting approach with immediate treatment with rituximab in adults with asymptomatic Stage II, III or IV follicular lymphoma (Grades 1, 2, 3a) and adequate bone marrow reserve. Of a total of 463 patients randomized between 2004 and 2009, 95% had low tumour burden (Groupe d étude des lymphomas folliculaires [GELF] criteria); the other 5% had raised lactase dehydrogenase (LDH) but fulfilled the other GELF criteria. Of the study participants, 98% were enrolled within 4 months of diagnostic biopsy. Median age of the patients was 60 years (range 27 87 years). Patient characteristics included: Eastern Cooperative Oncology Group (ECOG) performance status 0 (91%) and 1 (9%); Grade 1 2 (89%); Stage II (21%), Stage III (40%), Stage IV (39%); 42% with bone marrow involvement; Follicular Lymphoma International Prognostic Index (FLIPI) score 0 (9%), 1 (26%), 2 (41%), 3 (22%) and 4 (2%). Patients were randomly assigned to one of 3 study arms: watchful waiting (A, n=187); rituximab 375 mg/m 2 /week for 4 weeks (B, n=84); or rituximab 375 mg/m 2 /week for 4 weeks followed by rituximab maintenance every 2 months for 2 years (C, n=192). The primary endpoint was time to initiation of new therapy (TTINT), either chemotherapy or radiotherapy. Secondary endpoints included PFS, OS, 25-month response and frequency of spontaneous clinical remissions. The study was designed to detect an improvement of 18 months (30 48 months) in the median TTINT in the rituximab arms with 2.5% significance level and 90% power. A total of 230 events were required and 600 patients were planned. Arm B was discontinued in September 2007 because of clear evidence of the efficacy of maintenance rituximab. In the remaining two-arm comparison, 360 patients in A and C were planned, with a significance level of 5%. Mature data were analyzed in March 2010, with 36 patients still receiving rituximab maintenance. Table 3 presents data assessed at 7, 13 and 25 months for complete response (CR) or CR unconfirmed (CRu), partial response (PR) and overall response rate (ORR). Compulsory computed tomography (CT) scans were performed at months 7 and 25; bone marrow for histology and minimal residual Table 3: CT responses without bone marrow evaluation 7 months 13 months 25 months Arm A (watchful waiting) CR + CRu 3 (2%) 6 (3%) 5 (4%) PR 6 (3%) 7 (4%) 5 (4%) ORR 9 (5%) 13 (7%) 10 (8%) Arm B* (rituximab x 4 wk) CR + CRu 35 (43%) 36 (44%) 30 (40%) PR 25 (30%) 22 (27%) 10 (13%) ORR 60 (73%) 58 (71%) 40 (53%) Arm C* (rituximab x 4 wk + rituximab maintenance) CR + CRu 100 (54%) 122 (67%) 98 (70%) PR 61 (33%) 36 (20%) 12 (9%) ORR 161 (87%) 158 (87%) 110 (79%) χ 2 *p = 0.0216 *p = 0.0077 *p < 0.0001 CR=complete response CRu=CR unconfirmed PR=partial response ORR=overall response rate disease was required only if CT showed complete response. Of reported serious adverse events, 14 were considered related to the study drug: 5 allergic reactions (2 Grade 3), 6 infections, 3 episodes of Grade 3 4 neutropenia, and 1 neutropenic sepsis. At median followup of 32 months, new treatment (chemotherapy +/ rituximab 88%; radiotherapy 10%) was initiated in 83 (44%), 19 (23%) and 19 (10%) patients in A, B and C, respectively, with 78 (94%), 19 (100%) and 19 (100%) of these having progressed. Three-year PFS was 33%, 60% and 81%. The percentage of patients not requiring new treatment at 3 years was 48% in A, compared to 80% in B and 91% in C. HR were 0.37 (95% CI=0.25 0.56; p<0.001) for B vs A; 0.20 (95% CI=0.13 0.29; p<0.001) for C vs A); 0.57 (95% CI=0.29 1.12; p=0.10) for C vs B). The authors concluded that rituximab significantly improves TTINT and PFS survival in patients with asymptomatic follicular lymphoma compared with watchful waiting, and if QoL is no worse in rituximab arms then immediate treatment with rituximab is likely to prove a popular option with patients and their doctors as a new standard of care. oe VOL. 10, No. 1, february 2011 23

COMMENTARY: Conventional management of asymptomatic, low-tumour-burden, advanced-stage follicular lymphoma (FL) involves an initial period of watchful waiting, followed by repeated courses of chemotherapy at times of symptomatic disease progression. This approach is based on a few randomized controlled trials that demonstrated similar excellent survival rates with immediate or delayed chemotherapy after initial watchful waiting for these patients. 1-3 In view of the improved survival rates seen with chemoimmunotherapy using rituximab in regimens such as R-FCM (rituximab + fludarabine, cyclophosphamide, mitoxantrone), R-CVP (rituximab + cyclophosphamide, vincristine, prednisone) or R-CHOP (rituximab + cyclophosphamide, hydroxydoxorubicin, vincristine, prednisone) compared to chemotherapy alone, as well as the minimal toxicities seen with single-agent rituximab, lymphoma physicians became interested in a watchful waiting vs immediate rituximab study for FL patients. 4-6 Preliminary results of this study were reported at the 2010 American Society of Hematology meeting. The study achieved its primary endpoint by demonstrating significantly improved TTINT in the immediate rituximab arms (B and C). The median TTINT was 33 months in the watchful waiting arm, and although it was not reached in the rituximab arms, TTINT is projected to be further delayed by an additional 3 5 years. Such an improvement in TTINT may be sufficient for many patients and physicians to prefer immediate rituximab over watchful waiting. Optimistically, additional assumptions supporting this concept include the possibility that Arm B, which only involved rituximab x 4 doses, might actually be associated with lower overall cost of managing the disease, and may also delay treatment long enough for effective new non-chemotherapy options to become available. These conclusions meet with several major criticisms, however: IN BRIEF Already known Chemoimmunotherapy using rituximab in regimens such as R-FCM, R-CVP or R-CHOP improves survival rates in patients with asymptomatic FL compared to chemotherapy alone. What this study showed Immediate rituximab improved TTINT and PFS in this patient population compared with watchful waiting. Next steps Further study followup is needed before immediate rituximab/rituximab maintenance becomes standard of care for asymptomatic, low-tumour-burden, advanced-stage FL patients, to determine whether this approach improves overall survival compared to watchful waiting, and assesses its effect on QoL and cost of therapy. First, the only reasons to treat asymptomatic patients are either to improve OS rates and QoL, or to decrease cost of treatment. Since this study was not designed or powered to demonstrate improved OS, improved OS will likely never be shown. Further, although the study evaluated QoL, no QoL or pharmacoeconomic data have yet been reported. A second concern is that immediate rituximab may decrease the efficacy of subsequent chemoimmunotherapy when patients ultimately progress, by inducing rituximab resistance. Due to the current short median followup, the study cannot assess rates and duration of response to chemo immunotherapy and rituximab maintenance in patients who received immediate rituximab and later relapsed. Later reporting of results would have addressed this issue if the investigators had chosen a different primary endpoint for the study, such as time to second new treatment this would have permitted the evaluation of PFS following chemoimmunotherapy and rituximab maintenance after initial watchful waiting vs immediate rituximab. Third, immediate rituximab probably overtreats the 4 8% of patients who otherwise would have achieved spontaneous complete or partial remissions, and the 10 20% of patients who would not have needed chemotherapy by 10 years on watchful waiting alone. For these patients, at least, immediate rituximab would likely increase symptoms and cost of therapy compared with watchful waiting. A final concern is the inadequate justification for discontinuing accrual to Arm B. The investigators claimed that, for symptomatic patients with large-tumour-burden FL, overwhelming evidence supporting a role for maintenance rituximab following chemoimmunotherapy led them to discontinue Arm B, 7-9 but the issue may well be different in the setting of asymptomatic low-tumour-burden disease. Overall, it seems somewhat premature to change the standard of care from watchful waiting to immediate rituximab/ rituximab-maintenance for asymptomatic, low-tumour-burden, advanced-stage FL patients. That said, further study followup may potentially address many of the concerns listed above. If future updated results demonstrate improved QoL or pharmacoeconomics, and little impact on PFS following subsequent chemoimmunotherapy/rituximab maintenance for symptomatic progressive disease, the study may well result in a new standard of care for these patients. References 1. Young RC, Longo DL, Glatstein E et al. The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol 1988;25 (2 Suppl 2):11-6. 2. Brice P, Bastion Y, Lepage E et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'etude des Lymphomes Folliculaires. Groupe d'etude des Lymphomes de l'adulte. J Clin Oncol 1997;15:1110-7. 3. Ardeshna KM, Smith P, Norton A et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non- Hodgkin lymphoma: a randomised controlled trial. Lancet 2003;362:516-22. 4. Forstpointner R, Dreyling M, Repp R et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma 24 oe VOL. 10, No. 1, february 2011

Study Group. Blood 2004;104:3064-71. 5. Marcus R, Imrie K, Belch A et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105:1417-23. 6. Hiddemann W, Kneba M, Dreyling M et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005;106:3725-32. 7. van Oers MH, Klasa R, Marcus RE et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006;108:3295-301. 8. Dreyling M, Forstpointner R, Gramatzki M et al. Rituximab maintenance improves progression-free and overall survival rates after combined immunochemotherapy (R-FCM) in patients with relapsed follicular and mantle cell lymphoma: final results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 2006;24(18 Suppl):7502. 9. Salles GA, Seymour JF, Feugier P et al. Rituximab maintenance for 2 years in patients with untreated high tumor burden follicular lymphoma after response to immunochemotherapy. J Clin Oncol 2010; 28(15 Suppl):8004. Cancer-associated thrombosis Identification of patients at low risk for recurrent thrombosis M Dawn Goodyear, MD, MSc, FRCPC, Clinical Scholar, Division of Hematology and Hematologic Malignancies, University of Calgary. STUDY SUMMARY: Anticoagulant discontinuation in RVT-negative patients Siragusa S, Malato A, Mascheroni D et al. The optimal duration of anticoagulant therapy in patients with cancer-related deep vein thrombosis: The advantage of using residual vein thrombosis (the Cancer-DA- CUS Study). Blood (ASH Annual Meeting Abstracts). Nov 2010;116: Abstract 190. This study evaluated the role of a residual vein thrombosis (RVT)-based anticoagulation management with lowmolecular-weight heparin (LMWH) in cancer patients with acute deep vein thrombosis (DVT). Patients with active cancer and a first DVT episode were treated with LMWH for 1 month at full dosage followed by 5 months at a 25% dose reduction. Subsequently, those with RVT were randomized to either continue anticoagulants for 6 more months (Group A1) or discontinue (Group A2); patients without RVT stopped LMWH (Group B). Outcomes were recurrent venous thromboembolism and/or major bleeding, and patients were monitored for 1 year after LMWH discontinuation. Over 36 months, 409 patients were evaluated and 347 were included in the study. Baseline characteristics (age, sex, type of cancer) were similar in the 3 groups (see Table 4). RVT was detected in 242 (69.7%) patients; recurrent events occurred in 21.9% of those randomized to discontinue and 14.2% of those who continued LMWH. In patients without RVT (105, 30.3%), recurrent events occurred in 3 cases (2.8%). Adjusted Hazard Ratios (HR) for age and sex were 1.58 (95% confidence interval [CI]=0.85 2.93; p=0.145) between RVT groups (A2 vs A1), and 4.54 (CI=2.3 6.66; p=0.028) between groups A1 and B. Major bleeding events Table 4: Thrombotic occurrences in residual vein thrombosis (RVT)-positive vs RVT-negative patients Recurrences n/total (%) Recurrences n/100 person-yr (%) Recurrent VTE type DVT DVT + PE Isolated PE Contralateral Major bleeding, n/total (%) Major bleeding, n/100 person-yr (%) RVT-positive groups A1 A2 17/119 (14.2) 17/54.75 (31.0) 9 (52.9) 6 (35.3) 2 (11.7) 4 (23.5) 5/119 (4.2) 5/50.17 (9.9) 27/123 (21.9) 27/60.33 (44.7) 19 (70.3) 7 (25.9) 1 (3.7) 7 (25.9) 2/123 (1.6) 2/66.83 (2.9) *Chi-squared test unless specified; ** Fisher exact test VTE=venous thromboembolism DVT=deep vein thrombosis PE=pulmonary embolism RVT-negative group (B) 3/105 (2.8) P-values* 3/48.92 (6.1) 0.008 2 (66.6) 1 (33.3) 0 1 (33.3) 2/105 (1.9) 0.021 0.030 A1 vs B** 0.010 A2 vs B** 0.733 A1 vs A2** 0.054** 2/46.75 (4.2) 0.390 numbered 5, 2 and 2 in groups A1, A2 and B, respectively. Overall, 89 (25.6%) patients died due to cancer progression after median follow-up of 10.2 months after heparin withdrawal. According to final results of the Cancer-DACUS study, absence of RVT identifies patients at low risk for recurrent thrombosis who can safely stop LMWH after 6 months. COMMENTARY: The relationship between malignancy and VTE has been well described, with approximately 20% of all episodes of DVT occurring in people with an underlying malignancy. 1 Thrombosis is recognized as a significant cause of death in oncology patients in addition to being associated with an increased risk of recurrent VTE, bleeding complications, morbidity and utilization of health care resources. 2,3 Therapeutic doses of LMWH for a minimum oe VOL. 10, No. 1, february 2011 25

of 3 6 months is considered the standard treatment of acute thromboembolism in this setting. Unfortunately, the optimal long-term management is not well defined. There are few well designed clinical trials to guide treatment decisions beyond the acute period, particularly for patients with metastatic disease and those actively receiving chemotherapy, both considered to be at high risk of recurrent thrombosis. Furthermore, the financial costs incurred by patients receiving long-term anticoagulation with LMWH, in addition to the bleeding risk, often make it challenging to recommend continued therapy when little data exist to support its use beyond the initial treatment period. There has been recent interest in identifying objective markers that may be used to assist decision-making by stratifying patients based on the risk of a recurrent VTE. The authors of this study published the results of a similar study in 2008 (the DACUS Study) that involved noncancer patients with a first episode of DVT. 4 They randomized patients to continue or discontinue anticoagulation after 3 months of treatment based on the presence of RVT on compression ultrasonography. The adjusted HR for recurrent thromboembolism in patients with RVT vs those without was 24.9 (95% CI=3.4 183.6; p=0.002). This study provided support for the theory that assessment for RVT could be used to estimate the risk of a recurrent thrombotic event. Specifically, it showed that patients without evidence of RVT were at lower risk for developing a recurrence upon discontinuation of anticoagulation during the 1-year follow-up period. The Cancer-DACUS Study uses a similar methodology to the DACUS Study whereby the presence or absence of RVT was used to randomize patients to continue or discontinue anticoagulation. Patients with active malignancy who were confirmed to have a first episode of DVT were IN BRIEF Already known LMWH for a minimum of 3 6 months is standard treatment for acute thromboembolism in oncology patients but the optimal long-term management is not well defined. Assessment for RVT, in theory, can be used to estimate the risk of a recurrent thrombotic event. What this study showed Patients without evidence of RVT were at lower risk for developing a recurrence upon discontinuation of anticoagulation during a 1-year follow-up period. Next steps Further studies will determine the optimal use of RVT assessment in clinical practice. enrolled. The results of this study indicate that the presence of RVT, even in the setting of active cancer, can help identify patients who are at higher risk of developing a recurrent thrombotic event during the 1-year study period. Of the 242 patients with RVT on compression ultrasonography, there was no difference in the incidence of recurrent thrombosis, on or off anticoagulation (17 vs 27 respectively, p=0.733). In 105 patients with no evidence of RVT, 3 recurrent thrombotic events were seen upon discontinuation of anticoagulation. When compared to those with RVT, a statistically significant difference was shown with more thrombotic events seen in the RVT groups, with or without anticoagulation (p=0.021). Given that recurrent thrombotic events generally manifest in the same manner as the original event, the majority of recurrent events in all 3 study groups were DVT. As expected, the secondary outcome of major bleeding was highest in the group with RVT who continued anticoagulant therapy (5 vs 2 in each of the groups who had discontinued anticoagulation, p=0.054). The major limitation of the abstract as published is the absence of specific disease-associated demographic information, such as stage of malignancy and chemotherapy regimen received. Additional demographic information would allow a better assessment of the generalizability of the results. The concluding message for both the DACUS and Cancer-DACUS studies is that the absence of RVT can identify patients who are lower risk for recurrent thrombosis and as such, may safely discontinue anticoagulant therapy after the acute management. Although these results are encouraging, oncology patients have other variables, reflective of their disease state, which may influence the decision to discontinue anticoagulation. There was a higher portion of participants with advanced disease identified to have RVT than in the group without (A1 24.0% and A2 21.4% vs B 10.7%, p=0.03), suggesting that specific disease characteristics may also account for the increased incidence of recurrent thrombotic events. Nonetheless, in specific circumstances, such as in patients who are near completion of their cancer treatment or those who have had bleeding complications, the current body of evidence suggests that anticoagulation may be safely discontinued if diagnostic imaging shows no evidence of RVT. Further studies and data collection will be required to determine the optimal use of RVT assessment in clinical practice. References 1. Heit JA, O Fallon WM, Petterson TM et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 2002; 162(11): 1245-8. 2. Khorana AA, Francis CW, Culakova E et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007; 5:632-4. 3. Elting LS, Escalante CP, Cooksley C et al. Outcomes and cost of deep venous thrombosis among patients with cancer. Arch Intern Med 2004; 164:1653-61. 4. Siragusa S, Malato A, Anastasio R et al. Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the Duration of Anticoagulation based on Compression UltraSonography (DACUS) study. Blood 2008; 112:511-5. 26 oe VOL. 10, No. 1, february 2011

Hematopoietic stem cell transplantation Impact of in vivo T-cell depletion James Russell, MB, FRCP(Ed), Director, Alberta Blood & Marrow Transplant Program, Tom Baker Cancer Centre, Calgary. STUDY SUMMARY: In vivo T-cell depletion results in reduced GVHD but no improvement of DFS or OS. Soiffer RJ, LeRademacher, Ho VT et al. Impact of in vivo T-cell depletion on outcome of reduced intensity conditioning (RIC) hematopoietic cell transplantation (HCT) for hematologic malignancies. Blood (ASH Annual Meeting Abstracts). Nov 2010;116: Abstract 2305. This study compared transplant outcomes after in vivo T-cell depletion with antithymocyte globulin (ATG; n=584) and alemtuzumab (n=213) preparations to those with T-cell-replete (n=879) reduced-intensity-conditioning (RIC) transplants for myeloid and lymphoid malignancies. Median follow-up is 3 years in patients aged 21 69 years transplanted between 2000 2007. Conditioning regimens consisted of an alkylating agent (melphalan, busulfan or cyclophosphamide) with fludarabine. Of the patients, 792 (47%) received allografts from a human leukocyte antigen (HLA)-matched sibling; 650 (39%) from an 8/8; and 234 (14%) from a 7/8 HLA-matched unrelated donor. In vivo T-cell depletion was used for 35% of matched sibling hematopoietic cell transplantation (HCT); 57% of 8/8; and 64% of 7/8 HLA-matched unrelated donor HCT. Table 5 presents results of multivariable analysis adjusted for age, disease, disease stage, donor, transplant year, conditioning regimen and graft-versus-host disease (GVHD) prophylaxis. Grade 2 4 acute GVHD was lower with alemtuzumabcontaining (20%) than ATG-containing (41%) or T-cell-replete (42%) regimens. Chronic GVHD occurred in 27% of recipients of alemtuzumab, 43% of ATG and 57% of T-cell-replete regimens, respectively. Compared to T-cell-replete regimens, relapse risks were higher with ATG- and alemtuzumabcontaining regimens (38%, 49%, 51%, respectively); nonrelapse mortality was higher with ATG regimens only. Treatment failure (relapse or death) was higher with both ATG- and alemtuzumab-containing vs T-cell-replete regimens. Overall mortality was highest with ATG regimens. The Table 5. Transplant outcomes after alemtuzumab or antithymocyte globulin (ATG) T-cell depletion vs T-cell-replete regimens* Grade 2 4 acute GVHD Grade 3 4 acute GVHD Alemtuzumab vs T-cell-replete HR, p-value ATG vs T-cell-replete HR, p-value Alemtuzumab vs ATG HR, p-value 0.33, p<0.0001 0.88, p=0.12 0.38, p<0.001 0.42, p<0.0001 0.86, p=0.20 0.48, p=0.001 Chronic GVHD 0.34, p<0.0001 0.69, p<0.0001 0.49, p<0.0001 Non-relapse 1.04, p=0.85 1.34, p=0.01 0.78, p=0.19 mortality Relapse 1.54, p<0.0001 1.53, p<0.0001 1.01, p=0.94 Treatment failure 1.40, p=0.0003 1.46, p<0.0001 0.96, p=0.67 Overall mortality 1.09, p=0.46 1.25, p=0.002 0.87, p=0.22 * multivariable analysis adjusted for age, disease and disease stage, donor, year of transplant, conditioning regimen, and GVHD prophylaxis GVHD=graft-versus-host disease HR=hazard ratio 3-year probabilities of disease-free survival (DFS) were 25%, 30% and 39% with ATG-containing, alemtuzumab-containing and T-cell-replete regimens, respectively. Corresponding probabilities for overall survival were 38%, 50% and 46%. There were no differences in DFS and overall survival at 3 years by ATG source or dose. Incidence of Epstein-Barr virus posttransplantation lymphoproliferative disease (EBV-PTLD) was higher with alemtuzumab- and ATG-containing vs T-cellreplete regimens (2% vs 2% vs 0.2%). The study results indicate that in vivo T-cell depletion with RIC regimens containing an alkylating agent and fludarabine significantly lowers DFS despite lower GVHD. COMMENTARY: When allogeneic HCT was first introduced for the treatment of hematologic malignancies, it was based on the principle that the fully myeloablative conditioning regimens employed may be capable of eradicating the underlying disease but at the cost of complete ablation of the bone marrow. The allogeneic transplant was essentially used as a rescue procedure. In the subsequent 2 to 3 decades the curative potential of fully myeloablative transplants was established but at the cost of substantial transplant-related morbidity and mortality. We also learned that an immunologic graft-versusleukemia (GVL) mechanism contributed substantially to the therapeutic effect. This finding led to the development of so called nonmyeloablative and RIC regimens. It was thought that reducing the conditioning intensity would make allogeneic HCT more tolerable for older patients and those with comorbidities. More reliance would be placed on the GVL effect than the intensity of the conditioning to eradicate the leukemia. Engraftment would be facilitated by the newly developed purine analogs such as fludarabine plus the use of blood rather than bone marrow as a source of stem cells. One of the earlier RIC regimens developed by Slavin et al incorporated busulfan at half the conventional myeloablative dose in addition to fludarabine and ATG. 1 Since that time, many RIC regimens have incorporated ATG or alemtuzumab. The rationale was apparently to facilitate engraftment and to reduce the morbidity and mortality associated with both acute and chronic GVHD (agvhd and cgvhd). The study from the databases of the Centre for International oe VOL. 10, No. 1, february 2011 27

Blood and Marrow Transplant Research (CIBMTR) and the National Marrow Donor Program (NMDP) shows that while reducing GVHD, these techniques of in vivo T-cell depletion do not improve DFS or OS compared with regimens that use other agents to prevent GVHD. This finding should come as little surprise. First of all, there has never been evidence that in-vivo T-cell depletion is needed to facilitate engraftment in regimens where fludarabine is employed. Secondly, one would expect more relapse when using agents that will suppress the GVL effect when one is largely relying on this effect to deal with the underlying malignancy. The use of these agents could be justified if the effect on relapse was compensated for by reduced nonrelapse mortality (NRM). What the study has done is suggest that this may not be the case and that there may in fact be a disadvantage in terms of DFS for in-vivo T-cell depletion. The study did consider alemtuzumab, a monoclonal antibody, separately from ATG. However, the different polyclonal ATG preparations have very different potencies and mechanisms IN BRIEF Already known Many RIC transplants for myeloid and lymphoid malignancies incorporate ATG or alemtuzumab. What this study showed In vivo T-cell depletion with ATG or alemtuzumab does not improve DFS or OS vs T-cell-replete regimens Despite lowering GVHD, in vivo T-cell depletion does not reduce non-relapse moratlity. Next steps Determine if there is a survival advantage when ATG is used with fully myeloablative regimens. of action. We have also learned that dose and timing of ATG administration may critically influence clinical effects. The increased NRM attributable to ATG in this study may have been related to this issue but a more detailed analysis is required. This study should encourage transplant physicians to explore the appropriate use of these agents with a more critical eye. When ATG for example has been used with fully myeloablative regimens, there is substantial evidence that GVHD (particularly cgvhd) can be reduced and few, if any, studies have ever shown a survival disadvantage. 2 A recent randomized trial confirmed this effect on cgvhd although none on survival in patients given ATG Fresenius. 3 A randomized study by the Canadian Blood and Marrow Transplant Group is currently exploring the use of Thymoglobulin (a rabbit ATG) in unrelated donor transplantation. If survival is equivalent in this context, the argument for using in vivo T-cell depletion is strong because the quality of life of surviving patients will be improved if they have less GVHD. If these agents can be used to allow delivery of fully myeloablative regimens with a reduced NRM, this raises the possibility of escalating the dose intensity of the conditioning somewhat in order to compensate for the trend to more relapse. Preliminary studies have indicated that this may indeed be the case and some of the newer myeloablative regimens, particularly those incorporating full-dose busulfan with fludarabine with or without total body irradiation, may be delivered to patients who might otherwise be considered as candidates only for RIC or nonmyeloablative regimens. 4 References 1. Slavin S. Reduced-intensity conditioning or nonmyeloablative stem cell transplantation: introduction, rationale, and historic background. Semin Oncol 2004; 3:1-3. 2. Bacigalupo A. Antilymphocyte/thymocyte globulin for graft versus host disease prophylaxis: efficacy and side effects. Bone Marrow Transplant 2005;35:225-31. 3. Finke J, Bethge WA, Schmoor C et al. Standard graft-versus-host disease prophylaxis with or without anti-t-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol 2009;10:855-64. 4. Russell JA, Irish W, Balogh A et al. The addition of 400 cgy total body irradiation to a regimen incorporating once-daily intravenous busulfan, fludarabine, and antithymocyte globulin reduces relapse without affecting nonrelapse mortality in acute myelogenous leukemia. Biol Blood Marrow Transplant 2010;16:509-14. 28 oe VOL. 10, No. 1, february 2011