Dose intensity and the toxicity and efficacy of allogeneic hematopoietic cell transplantation

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1 (2005) 19, & 2005 Nature Publishing Group All rights reserved /05 $ KEYNOTE ADDRESS Dose intensity and the toxicity and efficacy of allogeneic hematopoietic cell transplantation 1 1 Fred Hutchinson Cancer Research Center and University of Washington School of Medicine, Seattle, WA, USA (2005) 19, doi: /sj.leu Introduction The intensity of the preparative regimen contributes to the overall toxicity and antitumor efficacy of allogeneic hematopoietic cell transplantation (HCT). However, other factors, principally graft-versus-host disease (GVHD) and its treatment, cause toxicity, and the graft-versus-tumor (GVT) effect of allogeneic transplantation is a key component of its efficacy. With the goal of developing an idealized preparative regimen, understanding the contribution of dose intensity to both the unfavorable and favorable outcomes of transplantation is important. However, in the past, it has been difficult to accurately determine the impact of dose on toxicity and efficacy because the majority of the preparative regimens in use were of similar intensity given the perceived need for a near-ablative dose of therapy to achieve engraftment. More recently, preclinical studies have shown that allogeneic engraftment can be achieved with relatively nontoxic approaches and the power of the GVT effect has been better appreciated. With these two advances, less-intensive preparative regimens have been developed and tested in large numbers of patients. This experience now allows a better understanding of the contributions of dose to the toxicity and efficacy of allogeneic HCT. intensity preparative regimens The fact that allogeneic engraftment can be achieved without myeloablation has been understood essentially since allogeneic transplantation was first achieved in humans. The very first successful allogeneic transplants for aplastic anemia were achieved following a conditioning regimen of 50 mg/kg cyclophosphamide on each of four consecutive days, a dose that was known to be less than myeloablative. 1 One of the earliest regimens used for successful allogeneic transplantation in leukemia, along with the now famous cyclophosphamide/ total body radiation (Cy/TBI) and busulfan/cyclophosphamide (Bu/Cy) regimens, was the BACT regimen, which combined BCNU with cytarabine, 6-thioguanine and cyclophosphamide. This same regimen was used without marrow support in the Correspondence: Dr, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue, N., D5-310, PO Box 19024, Seattle, WA , USA; Fax: ; fappelba@fhcrc.org This paper is part of a series of keynote addresses to be published in. They were presented at the Acute Forum, San Francisco, Friday April 16, 2004 Received 25 August 2004; accepted 21 October 2004 control arm of the first comparative study demonstrating the utility of cryopreserved autologous marrow, and full recovery was seen without marrow support, albeit after over 3 weeks of marrow aplasia. 2 Although the fact that allogeneic engraftment can be achieved with less than a fully myeloablative regimen has long been known, only in the mid to late 1990s did investigators begin to study in earnest the utility of preparative regimens of substantially less intensity. These studies were encouraged by a number of factors. Although the existence of an allogeneic GVT effect had been demonstrated more than 25 years ago, the effectiveness of donor lymphocyte infusions to induce remissions in patients who had relapsed after transplantation renewed interests in exploiting this aspect of allogeneic transplantation. 3,4 In addition, the mounting evidence of the effectiveness of allogeneic transplantation in the treatment of virtually all categories of hematologic malignancies in younger patients provided great incentive to try and find ways to gain a similar benefit in older individuals who often cannot tolerate the traditional transplant regimens. A number of different reduced-intensity preparative regimens have been explored. One of the initial and most widely used approaches is to combine modest doses of the highly immunosuppressive drug fludarabine with reasonably high but nonablative doses of melphalan, cyclophosphamide or busulfan. 5,6 Others have added anti-thymocyte globulin or CamPath s to these regimens to better insure engraftment. 7 Our group took advantage of preclinical data obtained from a canine model of transplantation where studies led by Storb et al showed that, somewhat surprisingly, the ability to obtain sustained allogeneic engraftment depended on the intensity of post-transplant immunosuppression delivered. In this model, sustained engraftment of marrow from histocompatible littermates required 9.2 Gy of TBI if no immunosuppression was administered post transplant, 4.5 Gy if cyclosporin (CSP) alone was given post transplant, but only 2.0 Gy if both CSP and mycophenolate mofetil (MMF) were given. 8 Based on these observations, the Seattle regimen of fludarabine 30 mg/m 2 /day for 3 days, followed by 2.0 Gy TBI and post-transplant administration of CSP and MMF was derived. 9 Several authors have attempted to order these various alternative regimens according to their intensity. Since each agent has its own specific spectrum of toxicities, such orderings are necessarily artificial and arbitrary. One way to order them is according to the degree of myelosuppression induced by the regimen. On this basis, among the reduced-intensity regiments, those including moderate dose busulfan are probably the most intensive, while the Seattle regimen is probably among the least. This ordering, however, ignores other nonhematologic toxicities. Nonetheless, since the goal of this paper is to begin to estimate the impact of dose intensity on the toxicities and

2 172 efficacy of allogeneic transplantation, a reasonable place to start is to compare one of the least aggressive regimens to standard ablative regimens. Thus, the following discussion on toxicity will focus on comparisons of the Seattle reduced-intensity regimen with standard Bu/Cy or Cy/TBI regimens. Contribution of dose intensity to toxicity in allogeneic HCT Hematopoietic toxicity Following administration of the Seattle regimen, peripheral counts drop slowly and, in fact, there is frequently engraftment and recovery of donor hematopoiesis before patients develop severe cytopenias. Thus, it is not surprising that hematopoietic toxicity is far less after use of this reduced-intensity preparative regimen. A comparison of the transfusion requirements of 40 patients given the reduced-intensity regimen with 67 concurrent case controls showed that 23% of the reduced-intensity recipients required platelet transfusions compared to 100% of controls (Po0.0001), and 63% required red cells compared to 96% of controls (Po0.0001). 10 The average number of platelets and red cell transfusions was substantially less in recipients of reduced-intensity preparative regimens (Table 1). Pulmonary toxicity The idiopathic pneumonia syndrome (IPS) seen after HCT is defined as widespread alveolar injury in the absence of active lower respiratory tract infection, and is widely assumed to be due, at least in part, to the toxicity of the preparative regimen. In a case control study, the incidence and outcome of IPS among patients who underwent reduced-intensity HCT using the Seattle regimen (N ¼ 183) was compared to 917 recipients of ablative transplants. 11 The cumulative incidence of IPS was 2.2% compared to 8.4% in controls (P ¼ 0.003) (see Figure 1). IPS was more frequent in older patients and those with severe acute GVHD. Once developed, the mortality from IPS was high (75%) with either preparative regimen approach. Gooley TA. Liver dysfunction and mortality after allogeneic marrow transplantation: analysis of 1419 consecutive patients. Hepatology 1999; October: 162A, #6, Abstract) Although significant bilirubin elevations are seen less frequently after reduced-intensity transplants, the prognosis is equally poor once this degree of jaundice occurs. Infectious complications Multiple factors contribute to the incidence of bacterial infections following allogeneic HCT, including neutropenia, damage to protective mucosal surfaces and immunosuppression. Thus, with reduced-intensity preparative regimens and the resultant decrease in neutropenia and damage to mucosa, a lower incidence of bacteremia would be expected. In a case control study of 56 recipients of reduced-intensity transplants compared to 112 controls, the incidence of bacteremias during the first 30 days was, as expected, significantly less (9 vs 27%, P ¼ 0.01). 13 When the analysis was extended to 100 days post transplant, the differences diminished (27 vs 41%, P ¼ 0.07) (Table 2). In contrast, when the incidence and outcome of invasive fungal infections were measured in 163 recipients of reducedintensity HCT and compared to recipients of ablative transplants, no differences were seen. 14 The cumulative incidences of invasive fungal infection, invasive mold infection, invasive aspergillosis and invasive candidiasis were 19, 15, 14 and 5%, Hepatic toxicity An analysis of 193 patients who underwent reduced-intensity HCT using the Seattle regimen found that 26% developed hyperbilirubinemia of 4 mg/dl or greater, usually due to GVHD or sepsis. No case of sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, was seen. 12 Overall survival at 1 year was far better in those without bilirubin elevations (78%) then in those with elevations of 4 mg/dl or greater (17 20%). For comparison, data from 1419 recipients of ablative transplants showed bilirubin levels of 4 mg/dl or greater in 48%, with SOS a frequent cause (McDonald GB, Schoch HG, Table 1 Transfusion requirements following reduced-intensity vs standard ablative conditioning regimens 10 intensity (N ¼ 40) (N ¼ 67) Median units red cells 2 (0 50) 6 (0 34) P ¼ Median units platelets 0 (0 214) 24 (4 358) Po Figure 1 Cumulative incidence of IPS following reduced-intensity (N ¼ 183) or conventional (N ¼ 917) preparative regimens for allogeneic transplantation. 11 Table 2 Infectious complications following reduced-intensity vs conventional preparation regimens for allogeneic transplantation Cumulative incidence intensity (%) (%) Bacterial infection by day P ¼ 0.01 Bacterial infection by day P ¼ 0.07 Invasive aspergillosis by 1 year P ¼ 0.30 CMV disease at 1 year (high risk patients only) P ¼ NS

3 respectively, and were not different from what was seen after conventional myeloablative HCT. These finding suggest that the early neutropenia and mucosal damage seen after ablative transplants are not major contributors to invasive fungal infection, but rather GVHD and its treatment are more important contributors. The incidence of CMV antigenemia, viremia and disease were analyzed in 56 recipients of reduced-intensity HCT and compared with 112 case controls transplanted in Seattle using myeloablative regimens over the same period of time. Although the onset of CMV reactivation and disease were delayed in recipients of reduced-intensity transplants, by 1 year post transplant, the overall incidence was similar. 15 Thus, recipients of reduced-intensity HCT should receive CMV surveillance beyond day 100, and treatment similar to that of recipients of ablative transplants. GVHD In animal models, the intensity of the preparative regimen has been shown to contribute to GVHD, presumably by inducing tissue damage and the elaboration of inflammatory cytokines. Thus, one might expect less GVHD after reduced-intensity preparative regimens. On the other hand, persistence of host antigen presenting cells for longer periods following reducedintensity transplants might favor a higher incidence of GVHD. A comparative study conducted in Seattle measured the incidence of GVHD in 44 recipients of reduced-intensity HCT and in 52 recipients of conventional ablative transplants. 16 The cumulative incidence of grades II IV acute GVHD was lower after reduced-intensity transplantation (64 vs 85%, P ¼ 0.001), but there was no difference in the cumulative incidence of chronic GVHD requiring treatment (73 vs 71%). More details are provided in Table 3. The onset of GVHD was delayed in recipients of reduced-intensity HCT, and in contrast to conventional transplant recipients, a syndrome of acute GVHD occurring after day 100 was seen in many patients. Overall morbidity and mortality The overall morbidity and mortality following human leukocyte antigen (HLA)-matched sibling HCT was compared in 73 recipients of reduced-intensity conditioning vs that seen in 73 recipients of conventional regimens. Using NCI Common Toxicity Criteria, the recipients of reduced-intensity regimens had significantly less severe toxicity in most organs/systems including hematologic, gastrointestinal, hepatic, hemorrhage, infection, metabolic, and pulmonary. 17 Overall, recipients of reduce-intensity regimens had a significantly lower incidence of Table 3 GVHD following reduced-intensity vs conventional transplantations 17 intensity (%) (%) Grades II IV acute GVHD by day 100 Matched siblings P ¼ 0.02 Matched URD P ¼ 0.01 Chronic GVHD Matched siblings P ¼ 0.37 Matched URD P ¼ 0.37 nonrelapse mortality at day 100 (3 vs 23%, P ¼ ) and at 1 year (16 vs 30%, P ¼ 0.04). A similar comparison was conducted between recipients of HLA-matched unrelated transplants following reduced-intensity (n ¼ 60) or conventional (n ¼ 74) regimens. 18 As was the case with HLA-matched sibling transplants, less severe toxicity was seen with the reduced-intensity regimen and this translated into a lower incidence of nonrelapse mortality at day 100 (12 vs 18%, P ¼ 0.07) and at 1 year (20 vs 32%, P ¼ 0.04). Retrospective case controlled studies are inherently plagued by concern of the comparability of the patient groups. An additional useful finding of the two studies just mentioned was that an assessment of pretransplant comorbidity using, in these specific examples, the Charlson Comorbidity Index was predictive of transplant outcome using either reduced-intensity or conventional regimens. Application of this sort of tool should prove useful in future studies when prospective randomized comparisons are not available. Contribution of intensity to antitumor effects in allogeneic HCT While there is no doubt that reduction in the intensity of the preparative regimen diminishes toxicities, it is more difficult to determine with any confidence the impact of reduction in intensity on the antitumor effects of such regimens. There are a number of reasons for this. First, even though reduced-intensity regimens have been used with increasing frequency over the last 5 years, the number of patients in any single disease category with adequate follow-up is quite limited, particularly when one starts to consider not just disease and stage, but also cytogenetic and other risk categories. Thus, there are simply not enough truly comparable patients in any one disease category with adequate follow-up to make careful retrospective comparison. Second, there may be subtle and not-so-subtle imbalances in any such comparisons. For example, recipients of reducedintensity transplants are generally older than recipients of conventional transplants, and recent studies suggest that even within specific subcategories of, for example, acute myeloid leukemia (AML), age may be an independent risk factor for disease resistance, a finding that would artificially favor more intensive regimens in retrospective comparisons. 19 On the other hand, most transplant experts assume that reduced-intensity regimens have less antitumor effects and thus avoid using such regimens in patients with obviously progressive acute leukemia and may also be more aggressive in the pretransplant treatment of patients in efforts to make them appropriate candidates for transplantation. Given the lack of adequate numbers of patients and these other inherit limitations, we need to look elsewhere for indications of the importance of regimen intensity on the antitumor effects of allogeneic HCT, at least for now. Effects of radiation dose Two randomized and one large nonrandomized trial have explored the importance of radiation dose on posttransplant relapse rates. In total, 71 patients with AML in first remission were treated with cyclophosphamide and either 12 Gy (n ¼ 34) or Gy (n ¼ 37) of TBI followed by HLA-matched sibling transplantation and methotrexate and cyclosporin as GVHD prophylaxis. 20 The relapse rate in the group receiving the lower TBI dose was 35% compared to 12% with the higher TBI dose (P ¼ 0.06). In a similar prospective randomized trial in patients 173

4 174 with chronic myeloid leukemia (CML) in chronic phase, the relapse rate in the 57 patients treated with the lower TBI dose was 25% compared to 0% in the 59 recipients of the higher TBI dose (P ¼ 0.008). 21 In both studies, nonrelapse mortality was higher with the higher TBI dose, thus balancing the reduction in relapse rates, with a result that in neither study overall survival was improved. Yet, these two prospective randomized studies argue that a relatively modest 30% increase in TBI can have a significant impact on relapse rates (see Table 4). Marks et al recently analyzed the outcome of 502 patients reported to the International Bone Marrow Transplant Registry following matched sibling transplantation for acute lymphoblastic leukemia (ALL) in first and second remission. They concluded that the TBI dose was the most significant factor they could identify for predicting relapse rates. Doses of TBI in excess of 13 Gy resulted in a 40% reduction in the chance of relapse (P ¼ 0.01), and also translated into a 37% reduction in the risk of death. 22 Effect of chemotherapy dose Despite the fact that allogeneic HCT has been a widely used form of therapy for treatment of hematologic malignancies for over three decades, there have been no prospective randomized studies examining the impact of different doses of chemotherapy in the preparative regimen. There is, however, some evidence that the dose of chemotherapy delivered to the tumor is important. In a study of 45 patients with CML in chronic phase undergoing transplantation from matched siblings following a preparative regimen of busulfan 16 mg/kg and cyclophosphamide 120 mg/kg, we found that there was considerable variability among patients in the average steady state of busulfan plasma concentration, presumably due to variability in patient absorption and metabolism. 23 The mean plasma concentration among patient was 971 ng/ml. Of interest for the present discussion was the observation that of the seven relapses seen among these patients, all occurred in the 23 patients whose steady-state busulfan concentration was below the mean (P ¼ ). More recently, de Lima et al 24 presented data from a retrospective analysis of 94 patients transplanted for AML or MDS suggesting that relapse rates were significantly less following a reduced-intensity conditioning regimen of fludarabine and busulfan than after a less-intensive nonablative regimen of fludarabine, cytarabine and idarubrin. Conclusions While we lack irrefutable evidence from ideally constructed large randomized trials, the available data argue convincingly that dose matters for both toxicity and antitumor efficacy, a conclusion that is hardly shocking or revolutionary. The impact of dose on toxicity extends beyond the predictable effects on acute organ damage, but may also influence the spectrum of infectious complications and the pattern of GVHD presentation Table 4 Relapse rates following Cy and either 12 or Gy TBI as preparation for allogeneic transplantation Relapse rates 12 Gy (%) Gy (%) AML CRI P ¼ 0.06 CML chronic phase P ¼ and development. The analysis of the effects of dose on antitumor response emphasizes that the allogeneic GVT effect is considerable but not unlimited, and that the influence of dose on tumor recurrence appears to apply to both radiation and to chemotherapy, and is not, apparently, limited to a single disease type, given results in AML, ALL and CML. While some have viewed reduced-intensity and conventional transplant approaches as competitive and mutually exclusive, that need not be the case and our job is to use the observable advantages of each to craft approaches that will ultimately be of greatest benefit for our patients. As our experience with reduced-intensity regimens grows, it may become possible to identify some patients for whom the minimally toxic reducedintensity approach is sufficient to eradicate the disease. Our current experience suggests that these patients will likely be those with earlier stages of indolent diseases such as CML in chronic phase (perhaps treated to cytogenetic remission with imatinib) or patients with recurrent indolent lymphomas and limited tumor burdens. For patients with more advanced diseases, a number of approaches are being explored that attempt to capitalize on our ability to achieve engraftment without fully ablative regimens. One approach is to incorporate additional chemotherapy into the reduced-intensity regimen, using, for example, moderate doses of busulfan or melphalan. Whether these regimens will provide overall gain by finding a happy medium between current conventional regimens and the more extreme forms of reduced-intensity regimens, or will, in fact lead to worse outcomes by increasing toxicity without a significant augmentation in tumor control, is unknown. A second approach that is being widely explored is to retain the dose intense therapy by first treating patients with relatively standard autologous transplant regimens, which can be delivered with overall mortality rates of less than 5%, and then proceeding in days with reduced-intensity allogeneic transplants in an effort to eliminate residual disease. Although time and resource consuming, and wearing on the patient, this approach shows considerable promise in a number of preliminary studies. For example, using a strategy of a melphalan autograft followed by reduced-intensity allograft, Maloney et al 25 reported an 83% overall response rate and a progression-free survival rate of 55% in 54 patients with multiple myeloma, half of whom had disease that had relapsed or was refractory to conventional chemotherapy. An additional strategy that acknowledges the importance of dose both in causing toxicity and in contributing to antitumor effects is to combine tumor-targeted therapy with a reducedintensity allogeneic transplant. For example, we have been studying an approach in which patients are first treated with I- 131 anti-cd45 monoclonal antibody, a reagent that delivers radiation specifically to hematopoietic tissue including marrow, spleen and lymph nodes while sparing normal organs, followed by administration of the standard Seattle reduced-intensity regimen of fludarabine plus 2 Gy TBI. In a dose escalation study, we have been able to deliver with the antibody-isotope 40 Gy to marrow and 56 Gy to spleen in combination with the reduced-intensity preparative regimen with no apparent increase in toxicity. A similar approach is being taken in selected lymphoma patients using a radiolabeled anti-cd20 antibody. These kinds of studies, as well as those conducted by many other investigators, give us considerable hope that we are approaching a day when we will have constructed an idealized transplant regimen consisting of targeted disease-specific therapy, specific immunosuppression to achieve engraftment, identification of the optimal donor and selective post-transplant immune reconstitution.

5 Acknowledgements This work was supported, in part, by grants CA 18029, CA 15704, CA 78902, and HL from the National Institutes of Health, DHHS. References 1 Storb R, Doney KC, Thomas ED, Appelbaum F, Buckner CD, Clift RA et al. Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients. Blood 1982; 59: Appelbaum FR, Herzig GP, Ziegler JL, Graw RG, Levine AS, Deisseroth AB. Successful engraftment of cryopreserved autologous bone marrow in patients with malignant lymphoma. Blood 1978; 52: Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 1979; 300: Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic. 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