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Clinical Trials of Adult T-Cell Leukaemia/Lymphoma Treatment

Clinical Trials of Adult T-Cell Leukaemia/Lymphoma Treatment Hindawi Publishing Corporation Leukemia Research and Treatment Volume 2012, Article ID 932175, 8 pages doi:10.1155/2012/932175 Review Article 1 1 1 2 1 Ambroise Marc¸ais, Felipe Suarez, David Sibon, Ali Bazarbachi, and Olivier Hermine Department of Hematology, Necker Hospital, 75473 Paris Cedex 15, France Department of Internal Medicine, American University of Beirut, Beirut, Lebanon Correspondence should be addressed to Olivier Hermine, ohermine@gmail.com Received 5 October 2011; Accepted 11 November 2011 Academic Editor: Kunihiro Tsukasaki Copyright © 2012 Ambroise Marc¸ais et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Adult T-cell leukaemia/lymphoma (ATLL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I (HTLV-1). Prognosis is severe because of intrinsic chemoresistance and severe immuosuppression. Four different subtypes are described with different outcomes, and treatment strategies vary according to the different clinical courses. Japanese trials show that combinations of chemotherapy can increase the response rates especially in the lymphoma subtype. However, patients have a high rate of relapse and the outcome remains extremely poor. Recently, a worldwide meta-analysis demonstrated that the combination of Zidovudine and Interferon-alpha (IFN) is effective in the leukemic subtypes (smoldering, chronic, and acute) and influences favorably the course of the disease. In order to prevent relapse, clinical trials testing new drugs such as monoclonal antibodies or combinations such as arsenic/IFN are needed. Finally, allogeneic stem cell transplantation is a feasible option but bears a very high rate of complications. 1. ATL Classification and Response Criteria Treatment of ATL is usually dependent on the ATL sub- type. Patients with aggressive forms (acute and lymphoma) The classification first described by Shimoyama (1991) have a very poor prognosis because of intrinsic chemore- used for the initial staging distinguishes four subtypes, sistance, a large tumor burden, hypercalcemia, and/or fre- which differ regarding their presentation and outcome. This quent infectious complications due to profound immune classification has been very useful for comparison between deficiency. Multiple Japanese trials in aggressive ATL clearly different studies [1]. demonstrated that although combinations of chemotherapy, The complex presentation with both leukemic and in particular those designed for treatment of aggressive non- lymphomatous components makes response assessment dif- Hodgkin lymphomas or acute lymphoblastic leukemia, have ficult. Recently, an international consensus meeting estab- improved the response rates particularly in ATL lymphoma, lished new response criteria [2]. they failed to achieve a significant impact on long-term Complete response (CR) is defined as the disappearance survival. Patients with indolent ATL (chronic or smoldering of all measurable tumor lesions (including normalization of subtypes) have a better prognosis. However, recent Japanese lymph node size) and normalization of absolute lymphocyte data showed a poor long-term outcome when patients are (including flower cells less than 5%) count below 4 × managed with a watchful-waiting policy until progression 109/L. Unconfirmed CR is defined as a reduction of 75% and even worse when patients are treated upfront with of the tumor size and normalization of absolute lymphocyte chemotherapy [3]. (including flower cells) count below 4 × 10 /L. Partial response (PR) is defined as a reduction of 50% of tumor 2. Conventional Chemotherapy size and absolute lymphocyte count. Progressive disease is defined as an increase of 50% of the tumor size and/or The Japan Clinical Oncology Group (JCOG) has conducted absolute lymphocyte count. These response criteria require six successive prospective clinical trials. All these trials are that each criterion is present for at least 4 weeks. based on conventional chemotherapy, with various dose 2 Leukemia Research and Treatment and administration modalities. The first trial JCOG 7801 (RIC) as a feasible treatment option for ATL patients. The used VEPA (a CHOP-like regimen that contained vincristine, largest retrospective study has been reported recently [8]. cyclophosphamide, prednisolone, doxorubicin). The CR rate This study includes 386 patients allografted between 1995 was only 17% with a median survival time of 5 months. The and 2005. After a median followup of 41 months, 3-year second trial, JCOG 8101, was a randomized phase III study, overallsurvivalwas 33%.Among patients whoreceived which included 54 patients and compared VEPA regimen related transplants, donor HTLV-I seropositivity adversely with VEPA-M (VEPA plus methotrexate) [4]. Although the affected disease-associated mortality. Recently, the long-term CR rate was improved in the VEPA-M group (37%), no results of a series of 30 patients who received an RIC was differences in median survival time (7.5 months) and overall reported. Overall survival rate and progression-free survival survival (8% at 4 years) were noted. rates were 36% (95% IC, 21 to 25%) and 31% (95% IC, 17 to The third trial, JCOG 8701, was a phase II study with 45%), respectively, [9]. However, the number of ATL patients a more aggressive regimen (LSG 4), which combined 3 eligible for alloSCT is very limited because of the low CR rate successive regimens: VEPA-B (VEPA plus bleomycin), M- especially in the acute form, poor performance status, severe VEPA (MTX, vindesine, cyclophosphamide, prednisolone, immunosuppression, age at disease (median age at onset: 60 doxorubicin), and VEPP-B (vincristine, etoposide, procar- years old), and low probability of finding suitable donors in bazine, prednisolone, and bleomycin). The CR rate was patients from ethnic minorities. improved to 42%. However, median survival rate and overall survival were poor with a median survival time (MST) of 8 4. Alpha Interferon (Zidovudine) AZT months and overall survival rate of 12% at 4 years. These trials enrolled also patients with other subtypes of NHL. Even if this treatment association is frequently referred MST was 44 months versus 8 months in the ATL group. to “antiviral therapy”, mechanism of action is not fully Following these initial trials, JCOG designed specific understood yet. The combination of Zidovudine (AZT) and regimens targeting ATL. The JCOG9109 trial (a phase II alphainterferon(IFN) wasfirstreportedin2phaseIIstudies study conducted between 1991 and 1993) used pentostatin- [10–12]. High response rate was observed particularly in containing regimen but did not show any improvement previously untreated acute ATL. The efficacy of this com- (MST 7.4 months and 2 years overall survival rate: 15%) [5]. bination was confirmed in a French trial using AZT/IFN JCOG 9303 was conducted between 1994 and 1996 in 19 newly diagnosed ATL patients, and in a UK clinical and used more intensive multiagent chemotherapy [6]. trial using AZT/IFN in 15 ATL patients [13, 14]. In a recent Treatment was designed as follows: VCAP (Vincristine, prospective Phase II study in the USA, 19 ATL patients cyclophosphamide, doxorubicin, prednisolone), AMP (Dox- received infusional chemotherapy (EPOCH regimen) until orubicin, ranimustine, prednisolone), and VCEP (vindesine, maximal response, followed by antiviral therapy with daily etoposide, carboplatin, prednisolone) and include intrathe- AZT, lamivudine, and IFN. However, because of disease cal injection of methotrexate and aracytine. The use of progression, only 6 patients received antiviral therapy [15]. Granulocyte Colony Stimulating Factor (GCSF) was system- A worldwide meta-analysis was recently performed on atic. Results were encouraging with a CR rate of 35%, an ATL survival since 1995 [16]. In this study, different treat- MST of 13 months versus 8 months with historical control ment strategies for ATL has been compared, namely, antiviral CHOP-like regimen. The 2-year OS was 31%. MCNU and therapy alone, chemotherapy alone, and chemotherapy fol- carboplatin were used because their activity is not affected by lowed by maintenance antiviral therapy in 254 ATL patients the expression of P-glycoprotein, a product of MDR1, which treated in the USA, the UK, Martinique, and continental is frequently expressed by ATLL cells. France (116 acute ATL, 18 chronic ATL, 11 smoldering ATL, In order to confirm these results, a phase III study and 100 ATL lymphoma). Five-year OS rates were 46% for 75 (JCOG9801) was conducted between 1998 and 2003. This patients who received first-line antiviral therapy, 20% for 77 study compared two arms of treatment: VCAP-AMP-VECP patients who received first-line chemotherapy, and 12% for versus biweekly CHOP. It included 118 patients (81 acute 55 patients who received first-line chemotherapy followed by subtype and 26 lymphoma subtype) [7]. Response rate antiviral therapy. was higher in the experimental arm (40% versus 25%). Patients with leukemic forms significantly benefited from Progression-free survival at 1 year was 28% versus 16%, and first-line antiviral therapy, whereas patients with ATL lym- overall survival was 24% versus 13%. There was a statistically phomahad abetteroutcome with chemotherapy.Inacute significant difference only in a subgroup analysis (patients ATL, first-line antiviral therapy alone resulted in a significant younger than 56 years old, poor PS). survival advantage (5-year OS of 28%) as compared with first-line chemotherapy with or without maintenance antivi- ral therapy (5-year OS of 10%). Achievement of CR with 3. Allogeneic Stem Cell Transplantation antiviral therapy resulted in 82% 5-year survival. In chronic As most of patients relapse after conventional chemotherapy, and smoldering ATL, antiviral therapy resulted in 100% 5- allogeneic stem cell transplantation (alloSCT) seems to be year survival. In ATL lymphoma, first-line antiviral therapy an attractive option as consolidation treatment. Most of resulted in a significant survival disadvantage (median and the reports come from Japan. A number of retrospective 5-year OS of 7 months and 0%, resp.) compared with first- studies have confirmed that alloSCT uses either myeloabla- line chemotherapy with or without maintenance antiviral tive conditioning (MAC) or reduced-intensity conditioning therapy (median and 5-year OS of 16 months and 18%, Leukemia Research and Treatment 3 resp.). Finally, a multivariate analysis confirmed that first- only preclinical studies have been performed (Hermine et al., line antiviral therapy significantly improves overall survival personal communication). of ATL patients (HR 0.47; 95% CI 0.27–0.83; P = 0.021). 7. Anti-CC Chemokine Receptor 4 (CCR4) 5. Arsenic Trioxide (AsO ) ATL cells express the CC chemokine receptor 4 (CCR4). Arsenic trioxide synergizes with IFN to induce cell cycle KW-0761 is a defucosylated humanized antibody with arrest and apoptosis in HTLV-I infected and fresh ATL enhanced antibody-dependent cellular cytotoxicity (ADCC) cells through rapid shut-off of the NF-κB pathway and a that binds CCR4. A phase I study reports 13 patients with delayed shut-off of cell cycle-associated genes, secondary CCR4-positive relapsed ATL treated with KW-0761. Overall to Tax degradation by the proteasome [17–19]. Although response rate (ORR) was 31%: 2 CRs and 2 PRs [26]. it has been demonstrated that arsenic and IFN cooperate A pivotal phase II study has been recently presented on to cure murine ATL derived from Tax transgenics through the 15th International Conference on Human retrovirology selective eradication of leukemia-initiating cell (LIC) activity. HTLV and related viruses. The primary end point was This strongly suggests that LIC activity is dependent on ORR. Twenty-eight patients with relapsed ATL were enrolled. continuous Tax oncogene expression. Hence, addition of Among the 26 pts evaluable for efficacy, the ORR was arsenic to AZT/IFN, through elimination of LIC activity, 50% with 8 CRs and 5 PRs with response rates in each may result in long-term disease eradication and potential affected lesion being 100% (13/13) for peripheral blood, cure [20]. Arecentprospective phaseIIstudy evaluated 63% (5/8) for skin, and 25% (3/12) for lymph node disease, the efficacy and safety of the combination of arsenic, IFN, respectively. The treatment schedule was one weekly perfu- and AZT in 10 newly diagnosed chronic ATL patients. The sion (1.0 mg/kg) for 8 weeks. Adverse events were mild to response rate was 100% including 7 CR, 2 CR but with moderate. more than 5% circulating atypical lymphocytes, and 1 partial response. Side effects were moderate and mostly hematologic 8. Watch-and-Wait Policy [21]. We have also recently reported a series of 11 patients with ATL (3 lymphoma type, 3 chronic, and 5 acute) Patients with smoldering or chronic ATLL subtype have a treated with arsenic/IFN after induction chemotherapy [22]. better prognosis than patients with aggressive forms (acute At initiation of AsO , 4 patients were in CR, 2 in PR, and lymphoma) and have been considered as indolent and 5 in progression. 10 patients received AsO during forms. Many patients have been managed with a watch- 3 to 8 weeks. One progressed 3 days after starting AsO and-wait policy until disease progression or treated with and 6 patients died. All were progressive at time of AsO chemotherapy when poor prognostic factors were present. initiation. 5 patients survived: 3-lymphoma type in CR (25, A recent published Japanese study reported 90 patients with 31, 46 months of followup), 1 acute in CR (9 months indolent form (65 chronic and 25 smoldering) [3]. Forty- followup), and 1 chronic in PR (39 months followup). four (49%) patients progressed to aggressive form with Tolerance was acceptable with peripheral neuropathy (n = a median time of transformation of 18.8 months (range 4), hand and foot syndrome (n = 3), and drug eruption 0.3 months to 17.6 years) and 41 died. Median survival (n = 3, including 2 toxic epidermolysis). While preliminary, time was 4.1 year. No difference between the two subtypes these observations nevertheless suggest that in ATL patients (chronic and smoldering) was observed. The estimated 10- arsenic/IFN efficiently targets ATL LIC activity and may be year survival rate was 25, 4% (95% CI, 15.3–36.8%). This useful as a consolidation therapy for those patients achieving study shows that even, in the indolent subtype, prognosis is a satisfactory response to induction therapy. poor. Moreover, patients who received chemotherapy had a worse prognosis and a shorter life expectancy than patients 6. Specific Monoclonal Antibodies who were treated was followed with watchful waiting. These results underscore the need for further improvement in ATL cells express CD25 (alpha-chain of IL2 receptor). A the treatment of patients with otherwise indolent forms of first trial reported use of antiCD25 antibody on 19 patients. ATL. Authors obtained 6 responses (two CR, four PR) that lasted from 9 weeks to more than 3 years [23]. 9. Agents That Have Shown Efficacy on T-Cell A second study used CD25 coupled with YTRIUM-90. Lymphoma outside HTLV-1 Infection Seven of 18 patients treated (one with chronic ATL and 6 with acute ATL) obtained a partial remission. The duration Currently, it is not yet clear whether or not T-cell lym- of these partial remissions ranged from 1.6 to 22.4 months phoproliferation associated with HTLV-1 infection is, with (mean, 9.2 months). Two patients achieved CR. One died respect to oncogenic mechanisms, different from other T-cell 36 months after initiation of therapy from a secondary AML lymphoma and as such whether or not they may benefit from and the other patient was still in CR at time of publication drugs approved or in the development in T-cell lymphoma. [24]. A neutralizing monoclonal antibody to the transferrin We discuss the potential benefit of five agents currently developed in the treatment of T-cell lymphomas: agents with receptor (mAb A24) has been designed and induces apop- tosis of ATLL cell lines and primary ATL cells [25]. Thus far, potential cytotoxic effect (pralatrexate and Bendamustine), 4 Leukemia Research and Treatment T-cell-targeted immunotherapy (Alemtuzumab) and agents Recently, romidepsin was evaluated on PTCL. A phase interacting with major cellular signaling pathways and/or 2 study reported forty-seven patients with PTCL of various viral homeostasis (Histone deacetylase inhibitors, Lenalido- subtypes including PTCL not otherwise specified (NOS), mide). AITL, ALK-negative anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma [30]. All patients received prior systemic therapies. Eighteen (38%) received 9.1. AntiFolate (Pralatrexate). Pralatrexate is a new antifolate stem cell transplantation. Overall response rate was 38% that was designed to be efficiently internalized by the reduced (95% confidence interval 24%–53%) with 8 CR and 9 folate carrier (RFC). A prospective study has shown its rela- PR. The median duration of overall response was 8.9 tive efficacy on 111 patients with relapse T-cell lymphoma months (range, 2–74). Moreover, 6 responses were observed [27]. Major lymphoma subtypes were peripheral T-cell among the 18 patients with prior alloSCT. Side effects were lymphoma (PTCL) and angio-immunoblastic T-lymphoma acceptable. (AITL). Only one patient in this study had an ATL. The To our knowledge, these drugs have not been yet response rate in 109 evaluable patients was 29% (32 of evaluated in ATL as a single therapy or in combination with 109), including 12 complete responses (11%) and 20 partial responses (18%), with a median duration of response of 10.1 other drugs in induction therapy. However, Ramos et al. have reported a clinical trial using IFN-AZT with valproic months. Median PFS and OS were, respectively, 3.5 and 14.5 months. The U.S. FDA approved Pralatrexate for cutaneous acid (HDAC inhibitor) during the maintenance treatment phase [31]. The authors hypothesized that HDAC inhibitors T-cell lymphoma (CTCL) in 2009. could reactivate latent HTLV-1 in ATLL cells harboring intact provirus and help eliminate residual disease. Thirteen 9.2. Histone Deacetylase Inhibitors (Vorinostat, Romidepsin, patients were enrolled. One showed a serial decrease in Panobinostat, and Belinostat). Histone deacetylase inhibitors clonal ATLL disease followed by PCR. Using fresh cells HDAC inhibitors (HDACI) are a new class of drugs whose from this patient treated ex vivo with Vorinostat, the activity was initially designed on transcriptional activity authors showed an increase of HTLV-1 expression and an by acting on chromatin epigenetic modification, histone induction of cell death. However, in this study, induction of deacetylation. However, their antitumor activity seems to a putative immune response against virus-infected cells was occur through others pathways. Indeed, it has been shown not addressed. that they also increase acetylation of other proteins such as nuclear transcription factors. Whatever the mechanism of action, exposure of cancer cells to HDAC inhibitors results 9.3. Monoclonal Antibody. Alemtuzumab (CAMPATH-1H) in growth arrest, cellular differentiation, and apoptosis. is an anti-CD52 antibody that is approved for chronic lymphoid leukemia treatment. It has been showed that it Two of these agents (vorinostat and romidepsin) have is effective on T-cell prolymphocytic leukemia with high been approved in the USA for the treatment of relapsed and response rate in a prospective study including 39 patients refractory CTCL. In these studies, they have been used as a with T-PLL treated with CAMPATH-1H [32]. The overall single agent. Studies are ongoing to evaluate their efficacy on response rate was 76% with 60% CR and 16% partial PTCL. remission (PR). These responses were durable with a median Vorinostat was evaluated in a phase II study. This study disease-free interval of 7 months (range, 4–45 months). included 74 pts with CTCL who had failed at least two In ATL, experience is limited to case report [33]. In prior systemic therapies [28]. The primary end point was addition, a recent study reported efficacy of the association overall response rate (ORR). ORR was 29.7%. Median time of alemtuzumab and pentostatin in various types of PTCL to objective response was 56 days (range, 28–171). Median including one case of ATL, which was in CR [34]. However, duration of response was not reached but estimated to be association Campath with conventional chemotherapy in more than 185 days (range, 34–441). Major side effects were PTCL has shown relative efficacy but high rate of infections. diarrhea (49%), fatigue (46%), nausea (43%), and anorexia (26%). Eleven patients required dose modification and nine discontinued due to adverse event. On the basis of this study, 9.4. Lenalidomide. Lenalidomide is a drug currently used the U.S. FDA approved Vorinostat for CTCL in October of for myeloma treatment. Studies have reported its use as 2006. single therapy for PTCL treatment. An interim report for a phase 2 clinical trial has been reported [35]. Patients Romidepsin was the second HDAC inhibitor that was with recurrent and refractory T-cell lymphomas other than approved by the U.S. FDA for CTCL in 2009. Two phase mycosis fungoides and untreated patients ineligible for com- 2 trials were conducted in patients with CTCL with the primary goal of determining response rate and tolerance bination chemotherapy were prescribed oral lenalidomide (25 mg daily) on Days 1 to 21 of each 28-day cycle until toxicity profile. The first trial included 71, and 96 patients were treated on a second trial. Response rates were 34% for disease progression. At the time of this interim analysis, 24 patients were enrolled in this study, and 23 were evaluable both studies with median durations of 13.7 and 15.4 months, respectively, [29]. Side effects that were acceptable included for response. The overall response rate was 7 (30%) of nausea, vomiting, fatigue, and transient thrombocytopenia 23; all were in partial responses. Two patients had stable and granulocytopenia. Romidepsin was approved for CTCL disease for ≥5 cycles. Median PFS was 96 days (range, 8– after these two studies. 696 days). Median OS was 241 days (range, 8–696 days). The Leukemia Research and Treatment 5 most common grade 4 adverse event was thrombocytopenia chemotherapy should be the preferred option. However, (33%). recent unpublished results from the UK suggest that com- bination of antiviral therapy with CHOP chemotherapy is superior to CHOP alone in patients with ATL lymphoma 9.5. Bendamustine. Bendamustine is a cytotoxic agent that [36]. Use of chemotherapy is based on the Japanese expe- has been recently approved for the treatment of CLL and rience across different trials. The LSG15 protocol is the indolent lymphoma such as follicular lymphoma. This “standard of care.” It is based on multiple drugs. When drug shows structural similarities with alkylating agents or treated with this LSG15 protocol, ATL lymphoma patients antimetabolites. A phase II study tests his efficacy on relapsed achieved a better CR rate (66.7%) than acute type (19.6%) or refractory peripheral T-cell lymphoma. The primary end or chronic type (40.0%). However, relapse occurs rapidly point is ORR (CR, CRu, PR). Preliminary results have been and overall survival rate is low [6]. Therefore, a consolida- shown recently for the first 38 patients (G. Damaj et al. 11th tion therapy is critical. Whenever possible, allogeneic SCT International Conference on Malignant Lymphoma, abstract should be considered [8]. For patient failing to achieve n 126). ORR was 47%: CR + CRu in 11 patients (29%), PR remission after chemotherapy or lacking a suitable donor, in 7 patients (18%). 20 patients experienced relapse. At the a consolidation strategy should be discussed. Based on time of analysis, the median duration time for responder preclinical data, ongoing clinical trials are testing the efficacy patients was 157 days (range, 14–350). The most adverse of two cycles of arsenic/IFN maintenance as a consolidation events (grade 3 and 4) were neutropenia and thrombopenia. procedure following achievement of CR with encouraging preliminary results [22]. Moreover, the addition of AZT/IFN 10. Strategy or other novel therapies to chemotherapy may help to achieve remission. HDAC inhibitor might be tested in this Suggested treatment strategies according to clinical presenta- indication to induce an immune response against residual tion are described in Figure 1. tumor cells. 10.1. Chronic and Smoldering ATL. Patients with chronic and smoldering ATL have a better prognosis compared to patients 10.3. Acute ATL. Combination chemotherapy regimens have with aggressive forms (acute and lymphoma). However, as little effect in acute ATL. Even if the most intensive regimen it has been shown in a recent Japanese study, long-term (LSG-15) have increased response rate, MST and OS are low survival is dismal when these patients are managed with a [6, 7]. In the recently published meta-analysis on antiviral watchful-waiting policy until disease progression. Moreover, therapy for ATL, treatment of acute ATL patients with AZT patients who received chemotherapy alone had a poorer and IFN showed a higher response rate and significantly outcome indicating that this may be detrimental in these prolonged survival. Moreover, patients who achieved CR subtypes [3]. So far, no clear prognostic factors have been yet had a long-term response [16]. Outside the context of defined in order to predict transformation to an aggressive clinical trials, the current standard therapy of acute ATL is form and treated patient who are at risk. combination therapy with AZT and IFN. However, it can Our point of view is that most of patients with chronic be difficult to manage patients presenting with bulky tumor and smoldering ATL should be treated. In the recent or severe hypercalcemia not responding to bisphopshonates, worldwide meta-analysis, patients with chronic/smoldering and initial chemotherapy is sometimes required. It would ATL who received first-line therapy by AZT-IFN only had an be helpful to predict which patients in the acute form excellent survival (100% OS beyond 5 years). Thus, outside will benefit from this approach. Preliminary results indicate the context of clinical trials, the current standard therapy of that patients with wild-type functional p53 are more likely chronic and smoldering ATL is combination therapy with to respond to AZT/IFN combination [37]. We, therefore, AZT and IFN. This requires, however, continuous therapy. recommend evaluating p53 by a functional assay in all Treatment should not be interrupted as relapse always occurs patients while the treatment is initiated [38]. Long-term when treatment is stopped. The recommended starting disease control requires, however, continuous therapy, since dose is AZT 600 to 900 mg/day (in 3 divided doses) and relapse is always noted when treatment is stopped. The interferon-alpha (5 to 6 million IU/m2/day). Usually, after recommended dose is the same as with chronic/smoldering one month, AZT dose can be titrated down to 600 mg/day form.Asinlymphomasubtype,allogeneicHSCTshould in 2 divided doses and IFN dose can be reduced to 3 to 5 be considered for young patients with acute ATL and a million IU/day or alternatively 1.5 μg/kg of pegylated IFN suitable donor [38]. As in other ATL subtype, based on weekly. Based on preclinical studies, clinical trials are testing preclinical data, ongoing clinical trials are testing the efficacy the effect of adding arsenic to the AZT/IFN combination as a of arsenic/IFN maintenance following achievement of CR. consolidation therapy with the aim of then stopping therapy and achieving cure by potential elimination of leukaemia- 10.4. Supportive Therapy in ATL. Hypercalcaemia associated intiating cells [17–20]. with aggressive ATL should be managed with treatment of the disease, hydration, and bisphosphonate therapy. 10.2. ATL Lymphoma. As has been shown in the recent meta- Trimethoprim-sulfamethoxazole, valacyclovir, and antifun- analysis, the combination AZT-IFN is less effective than gal agents are recommended for the prophylaxis of Pneumo- first-line chemotherapy in ATL lymphoma [16]. Therefore, cystis jiroveci pneumonia, herpes simplex virus, and fungal 6 Leukemia Research and Treatment Induction therapy Maintenance IFN-AZT Smoldering/ IFN-AZT Addition of trioxide arsenic to eradicate MRD chronic or HDAC inhibitor (to be tested in clinical trials) Chemotherapy alloSCT if feasible ATL lymphoma LSG 15 protocol IFN-AZT intrathecal chemotherapy Addition of trioxide arsenic to eradicate MRD IFN-AZT CR Addition of trioxide arsenic to eradicate MRD IFN-AZT Response ATL acute intrathecal chemotherapy alloSCT if feasible at 2 months P53 screening No CR Clinical trials testing new drugs Figure 1: Recommended treatment strategy for patients with acute, lymphoma, or chronic/smoldering ATL (CR: complete remission; MRD: minimal residual disease; AZT: zidovudine; IFN: interferon-alpha; alloSCT: allogeneic stem cell transplantation). infections, respectively; in the Japanese Trials, prophylaxis regimen but constantly relapse and have a poor prognosis. with antistrongyloides agents, such as ivermectin or alben- Addition of AZT-IFN in combination with chemotherapy dazole, should be considered in order to avoid systemic may increase response rate but its long-term effect remains infection in patients with a history of past and/or present to be determined. We recommend, for those in whom exposure to the parasite. Intrathecal prophylaxis should be alloSCT is not feasible, that a consolidation treatment with considered for patients with aggressive ATL even in the AsO is considered, followed by maintenance therapy with absence of clinical symptoms because more than half of AZT/IFN. This approach should be tested in future clinical relapses at new site after chemotherapy occur in the central trials. Prophylaxis of opportunistic infections and supportive nervous system. therapy are mandatory. In order to prevent the occurrence of resistance and relapse, clinical trials assessing additional targeted therapies such as arsenic/IFN combination or 11. Conclusion monoclonal antibodies, particularly the promising anti- The combination of AZT and IFN is highly effective in CCR4 antibodies, are mandatory after achieving CR. Finally, the leukemic subtypes of ATL and should be considered as allogeneic SCT should be considered in suitable patients. standard in first-line therapy in that setting. This combina- HDAC inhibitor may be also an interesting option. Currently, tion has clearly changed the natural history of the disease due to the poor outcome of patients with aggressive ATL through achievement of a significantly improved long-term (acute and lymphoma forms), phase II studies are mandatory survival in patients with smoldering and chronic ATL as in the near future. In chronic form, it is time to set up phase well as a subset of patients with acute ATL. Prior exposure III studies to assess new drugs to avoid relapse for patients to chemotherapy increases the rate of complications and of treated with AZT-IFN. acquiring p53 mutations. 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Clinical Trials of Adult T-Cell Leukaemia/Lymphoma Treatment

Leukemia Research and Treatment , Volume 2012 – Feb 14, 2012

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Copyright © 2012 Ambroise Marçais et al.
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10.1155/2012/932175
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Abstract

Hindawi Publishing Corporation Leukemia Research and Treatment Volume 2012, Article ID 932175, 8 pages doi:10.1155/2012/932175 Review Article 1 1 1 2 1 Ambroise Marc¸ais, Felipe Suarez, David Sibon, Ali Bazarbachi, and Olivier Hermine Department of Hematology, Necker Hospital, 75473 Paris Cedex 15, France Department of Internal Medicine, American University of Beirut, Beirut, Lebanon Correspondence should be addressed to Olivier Hermine, ohermine@gmail.com Received 5 October 2011; Accepted 11 November 2011 Academic Editor: Kunihiro Tsukasaki Copyright © 2012 Ambroise Marc¸ais et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Adult T-cell leukaemia/lymphoma (ATLL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I (HTLV-1). Prognosis is severe because of intrinsic chemoresistance and severe immuosuppression. Four different subtypes are described with different outcomes, and treatment strategies vary according to the different clinical courses. Japanese trials show that combinations of chemotherapy can increase the response rates especially in the lymphoma subtype. However, patients have a high rate of relapse and the outcome remains extremely poor. Recently, a worldwide meta-analysis demonstrated that the combination of Zidovudine and Interferon-alpha (IFN) is effective in the leukemic subtypes (smoldering, chronic, and acute) and influences favorably the course of the disease. In order to prevent relapse, clinical trials testing new drugs such as monoclonal antibodies or combinations such as arsenic/IFN are needed. Finally, allogeneic stem cell transplantation is a feasible option but bears a very high rate of complications. 1. ATL Classification and Response Criteria Treatment of ATL is usually dependent on the ATL sub- type. Patients with aggressive forms (acute and lymphoma) The classification first described by Shimoyama (1991) have a very poor prognosis because of intrinsic chemore- used for the initial staging distinguishes four subtypes, sistance, a large tumor burden, hypercalcemia, and/or fre- which differ regarding their presentation and outcome. This quent infectious complications due to profound immune classification has been very useful for comparison between deficiency. Multiple Japanese trials in aggressive ATL clearly different studies [1]. demonstrated that although combinations of chemotherapy, The complex presentation with both leukemic and in particular those designed for treatment of aggressive non- lymphomatous components makes response assessment dif- Hodgkin lymphomas or acute lymphoblastic leukemia, have ficult. Recently, an international consensus meeting estab- improved the response rates particularly in ATL lymphoma, lished new response criteria [2]. they failed to achieve a significant impact on long-term Complete response (CR) is defined as the disappearance survival. Patients with indolent ATL (chronic or smoldering of all measurable tumor lesions (including normalization of subtypes) have a better prognosis. However, recent Japanese lymph node size) and normalization of absolute lymphocyte data showed a poor long-term outcome when patients are (including flower cells less than 5%) count below 4 × managed with a watchful-waiting policy until progression 109/L. Unconfirmed CR is defined as a reduction of 75% and even worse when patients are treated upfront with of the tumor size and normalization of absolute lymphocyte chemotherapy [3]. (including flower cells) count below 4 × 10 /L. Partial response (PR) is defined as a reduction of 50% of tumor 2. Conventional Chemotherapy size and absolute lymphocyte count. Progressive disease is defined as an increase of 50% of the tumor size and/or The Japan Clinical Oncology Group (JCOG) has conducted absolute lymphocyte count. These response criteria require six successive prospective clinical trials. All these trials are that each criterion is present for at least 4 weeks. based on conventional chemotherapy, with various dose 2 Leukemia Research and Treatment and administration modalities. The first trial JCOG 7801 (RIC) as a feasible treatment option for ATL patients. The used VEPA (a CHOP-like regimen that contained vincristine, largest retrospective study has been reported recently [8]. cyclophosphamide, prednisolone, doxorubicin). The CR rate This study includes 386 patients allografted between 1995 was only 17% with a median survival time of 5 months. The and 2005. After a median followup of 41 months, 3-year second trial, JCOG 8101, was a randomized phase III study, overallsurvivalwas 33%.Among patients whoreceived which included 54 patients and compared VEPA regimen related transplants, donor HTLV-I seropositivity adversely with VEPA-M (VEPA plus methotrexate) [4]. Although the affected disease-associated mortality. Recently, the long-term CR rate was improved in the VEPA-M group (37%), no results of a series of 30 patients who received an RIC was differences in median survival time (7.5 months) and overall reported. Overall survival rate and progression-free survival survival (8% at 4 years) were noted. rates were 36% (95% IC, 21 to 25%) and 31% (95% IC, 17 to The third trial, JCOG 8701, was a phase II study with 45%), respectively, [9]. However, the number of ATL patients a more aggressive regimen (LSG 4), which combined 3 eligible for alloSCT is very limited because of the low CR rate successive regimens: VEPA-B (VEPA plus bleomycin), M- especially in the acute form, poor performance status, severe VEPA (MTX, vindesine, cyclophosphamide, prednisolone, immunosuppression, age at disease (median age at onset: 60 doxorubicin), and VEPP-B (vincristine, etoposide, procar- years old), and low probability of finding suitable donors in bazine, prednisolone, and bleomycin). The CR rate was patients from ethnic minorities. improved to 42%. However, median survival rate and overall survival were poor with a median survival time (MST) of 8 4. Alpha Interferon (Zidovudine) AZT months and overall survival rate of 12% at 4 years. These trials enrolled also patients with other subtypes of NHL. Even if this treatment association is frequently referred MST was 44 months versus 8 months in the ATL group. to “antiviral therapy”, mechanism of action is not fully Following these initial trials, JCOG designed specific understood yet. The combination of Zidovudine (AZT) and regimens targeting ATL. The JCOG9109 trial (a phase II alphainterferon(IFN) wasfirstreportedin2phaseIIstudies study conducted between 1991 and 1993) used pentostatin- [10–12]. High response rate was observed particularly in containing regimen but did not show any improvement previously untreated acute ATL. The efficacy of this com- (MST 7.4 months and 2 years overall survival rate: 15%) [5]. bination was confirmed in a French trial using AZT/IFN JCOG 9303 was conducted between 1994 and 1996 in 19 newly diagnosed ATL patients, and in a UK clinical and used more intensive multiagent chemotherapy [6]. trial using AZT/IFN in 15 ATL patients [13, 14]. In a recent Treatment was designed as follows: VCAP (Vincristine, prospective Phase II study in the USA, 19 ATL patients cyclophosphamide, doxorubicin, prednisolone), AMP (Dox- received infusional chemotherapy (EPOCH regimen) until orubicin, ranimustine, prednisolone), and VCEP (vindesine, maximal response, followed by antiviral therapy with daily etoposide, carboplatin, prednisolone) and include intrathe- AZT, lamivudine, and IFN. However, because of disease cal injection of methotrexate and aracytine. The use of progression, only 6 patients received antiviral therapy [15]. Granulocyte Colony Stimulating Factor (GCSF) was system- A worldwide meta-analysis was recently performed on atic. Results were encouraging with a CR rate of 35%, an ATL survival since 1995 [16]. In this study, different treat- MST of 13 months versus 8 months with historical control ment strategies for ATL has been compared, namely, antiviral CHOP-like regimen. The 2-year OS was 31%. MCNU and therapy alone, chemotherapy alone, and chemotherapy fol- carboplatin were used because their activity is not affected by lowed by maintenance antiviral therapy in 254 ATL patients the expression of P-glycoprotein, a product of MDR1, which treated in the USA, the UK, Martinique, and continental is frequently expressed by ATLL cells. France (116 acute ATL, 18 chronic ATL, 11 smoldering ATL, In order to confirm these results, a phase III study and 100 ATL lymphoma). Five-year OS rates were 46% for 75 (JCOG9801) was conducted between 1998 and 2003. This patients who received first-line antiviral therapy, 20% for 77 study compared two arms of treatment: VCAP-AMP-VECP patients who received first-line chemotherapy, and 12% for versus biweekly CHOP. It included 118 patients (81 acute 55 patients who received first-line chemotherapy followed by subtype and 26 lymphoma subtype) [7]. Response rate antiviral therapy. was higher in the experimental arm (40% versus 25%). Patients with leukemic forms significantly benefited from Progression-free survival at 1 year was 28% versus 16%, and first-line antiviral therapy, whereas patients with ATL lym- overall survival was 24% versus 13%. There was a statistically phomahad abetteroutcome with chemotherapy.Inacute significant difference only in a subgroup analysis (patients ATL, first-line antiviral therapy alone resulted in a significant younger than 56 years old, poor PS). survival advantage (5-year OS of 28%) as compared with first-line chemotherapy with or without maintenance antivi- ral therapy (5-year OS of 10%). Achievement of CR with 3. Allogeneic Stem Cell Transplantation antiviral therapy resulted in 82% 5-year survival. In chronic As most of patients relapse after conventional chemotherapy, and smoldering ATL, antiviral therapy resulted in 100% 5- allogeneic stem cell transplantation (alloSCT) seems to be year survival. In ATL lymphoma, first-line antiviral therapy an attractive option as consolidation treatment. Most of resulted in a significant survival disadvantage (median and the reports come from Japan. A number of retrospective 5-year OS of 7 months and 0%, resp.) compared with first- studies have confirmed that alloSCT uses either myeloabla- line chemotherapy with or without maintenance antiviral tive conditioning (MAC) or reduced-intensity conditioning therapy (median and 5-year OS of 16 months and 18%, Leukemia Research and Treatment 3 resp.). Finally, a multivariate analysis confirmed that first- only preclinical studies have been performed (Hermine et al., line antiviral therapy significantly improves overall survival personal communication). of ATL patients (HR 0.47; 95% CI 0.27–0.83; P = 0.021). 7. Anti-CC Chemokine Receptor 4 (CCR4) 5. Arsenic Trioxide (AsO ) ATL cells express the CC chemokine receptor 4 (CCR4). Arsenic trioxide synergizes with IFN to induce cell cycle KW-0761 is a defucosylated humanized antibody with arrest and apoptosis in HTLV-I infected and fresh ATL enhanced antibody-dependent cellular cytotoxicity (ADCC) cells through rapid shut-off of the NF-κB pathway and a that binds CCR4. A phase I study reports 13 patients with delayed shut-off of cell cycle-associated genes, secondary CCR4-positive relapsed ATL treated with KW-0761. Overall to Tax degradation by the proteasome [17–19]. Although response rate (ORR) was 31%: 2 CRs and 2 PRs [26]. it has been demonstrated that arsenic and IFN cooperate A pivotal phase II study has been recently presented on to cure murine ATL derived from Tax transgenics through the 15th International Conference on Human retrovirology selective eradication of leukemia-initiating cell (LIC) activity. HTLV and related viruses. The primary end point was This strongly suggests that LIC activity is dependent on ORR. Twenty-eight patients with relapsed ATL were enrolled. continuous Tax oncogene expression. Hence, addition of Among the 26 pts evaluable for efficacy, the ORR was arsenic to AZT/IFN, through elimination of LIC activity, 50% with 8 CRs and 5 PRs with response rates in each may result in long-term disease eradication and potential affected lesion being 100% (13/13) for peripheral blood, cure [20]. Arecentprospective phaseIIstudy evaluated 63% (5/8) for skin, and 25% (3/12) for lymph node disease, the efficacy and safety of the combination of arsenic, IFN, respectively. The treatment schedule was one weekly perfu- and AZT in 10 newly diagnosed chronic ATL patients. The sion (1.0 mg/kg) for 8 weeks. Adverse events were mild to response rate was 100% including 7 CR, 2 CR but with moderate. more than 5% circulating atypical lymphocytes, and 1 partial response. Side effects were moderate and mostly hematologic 8. Watch-and-Wait Policy [21]. We have also recently reported a series of 11 patients with ATL (3 lymphoma type, 3 chronic, and 5 acute) Patients with smoldering or chronic ATLL subtype have a treated with arsenic/IFN after induction chemotherapy [22]. better prognosis than patients with aggressive forms (acute At initiation of AsO , 4 patients were in CR, 2 in PR, and lymphoma) and have been considered as indolent and 5 in progression. 10 patients received AsO during forms. Many patients have been managed with a watch- 3 to 8 weeks. One progressed 3 days after starting AsO and-wait policy until disease progression or treated with and 6 patients died. All were progressive at time of AsO chemotherapy when poor prognostic factors were present. initiation. 5 patients survived: 3-lymphoma type in CR (25, A recent published Japanese study reported 90 patients with 31, 46 months of followup), 1 acute in CR (9 months indolent form (65 chronic and 25 smoldering) [3]. Forty- followup), and 1 chronic in PR (39 months followup). four (49%) patients progressed to aggressive form with Tolerance was acceptable with peripheral neuropathy (n = a median time of transformation of 18.8 months (range 4), hand and foot syndrome (n = 3), and drug eruption 0.3 months to 17.6 years) and 41 died. Median survival (n = 3, including 2 toxic epidermolysis). While preliminary, time was 4.1 year. No difference between the two subtypes these observations nevertheless suggest that in ATL patients (chronic and smoldering) was observed. The estimated 10- arsenic/IFN efficiently targets ATL LIC activity and may be year survival rate was 25, 4% (95% CI, 15.3–36.8%). This useful as a consolidation therapy for those patients achieving study shows that even, in the indolent subtype, prognosis is a satisfactory response to induction therapy. poor. Moreover, patients who received chemotherapy had a worse prognosis and a shorter life expectancy than patients 6. Specific Monoclonal Antibodies who were treated was followed with watchful waiting. These results underscore the need for further improvement in ATL cells express CD25 (alpha-chain of IL2 receptor). A the treatment of patients with otherwise indolent forms of first trial reported use of antiCD25 antibody on 19 patients. ATL. Authors obtained 6 responses (two CR, four PR) that lasted from 9 weeks to more than 3 years [23]. 9. Agents That Have Shown Efficacy on T-Cell A second study used CD25 coupled with YTRIUM-90. Lymphoma outside HTLV-1 Infection Seven of 18 patients treated (one with chronic ATL and 6 with acute ATL) obtained a partial remission. The duration Currently, it is not yet clear whether or not T-cell lym- of these partial remissions ranged from 1.6 to 22.4 months phoproliferation associated with HTLV-1 infection is, with (mean, 9.2 months). Two patients achieved CR. One died respect to oncogenic mechanisms, different from other T-cell 36 months after initiation of therapy from a secondary AML lymphoma and as such whether or not they may benefit from and the other patient was still in CR at time of publication drugs approved or in the development in T-cell lymphoma. [24]. A neutralizing monoclonal antibody to the transferrin We discuss the potential benefit of five agents currently developed in the treatment of T-cell lymphomas: agents with receptor (mAb A24) has been designed and induces apop- tosis of ATLL cell lines and primary ATL cells [25]. Thus far, potential cytotoxic effect (pralatrexate and Bendamustine), 4 Leukemia Research and Treatment T-cell-targeted immunotherapy (Alemtuzumab) and agents Recently, romidepsin was evaluated on PTCL. A phase interacting with major cellular signaling pathways and/or 2 study reported forty-seven patients with PTCL of various viral homeostasis (Histone deacetylase inhibitors, Lenalido- subtypes including PTCL not otherwise specified (NOS), mide). AITL, ALK-negative anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma [30]. All patients received prior systemic therapies. Eighteen (38%) received 9.1. AntiFolate (Pralatrexate). Pralatrexate is a new antifolate stem cell transplantation. Overall response rate was 38% that was designed to be efficiently internalized by the reduced (95% confidence interval 24%–53%) with 8 CR and 9 folate carrier (RFC). A prospective study has shown its rela- PR. The median duration of overall response was 8.9 tive efficacy on 111 patients with relapse T-cell lymphoma months (range, 2–74). Moreover, 6 responses were observed [27]. Major lymphoma subtypes were peripheral T-cell among the 18 patients with prior alloSCT. Side effects were lymphoma (PTCL) and angio-immunoblastic T-lymphoma acceptable. (AITL). Only one patient in this study had an ATL. The To our knowledge, these drugs have not been yet response rate in 109 evaluable patients was 29% (32 of evaluated in ATL as a single therapy or in combination with 109), including 12 complete responses (11%) and 20 partial responses (18%), with a median duration of response of 10.1 other drugs in induction therapy. However, Ramos et al. have reported a clinical trial using IFN-AZT with valproic months. Median PFS and OS were, respectively, 3.5 and 14.5 months. The U.S. FDA approved Pralatrexate for cutaneous acid (HDAC inhibitor) during the maintenance treatment phase [31]. The authors hypothesized that HDAC inhibitors T-cell lymphoma (CTCL) in 2009. could reactivate latent HTLV-1 in ATLL cells harboring intact provirus and help eliminate residual disease. Thirteen 9.2. Histone Deacetylase Inhibitors (Vorinostat, Romidepsin, patients were enrolled. One showed a serial decrease in Panobinostat, and Belinostat). Histone deacetylase inhibitors clonal ATLL disease followed by PCR. Using fresh cells HDAC inhibitors (HDACI) are a new class of drugs whose from this patient treated ex vivo with Vorinostat, the activity was initially designed on transcriptional activity authors showed an increase of HTLV-1 expression and an by acting on chromatin epigenetic modification, histone induction of cell death. However, in this study, induction of deacetylation. However, their antitumor activity seems to a putative immune response against virus-infected cells was occur through others pathways. Indeed, it has been shown not addressed. that they also increase acetylation of other proteins such as nuclear transcription factors. Whatever the mechanism of action, exposure of cancer cells to HDAC inhibitors results 9.3. Monoclonal Antibody. Alemtuzumab (CAMPATH-1H) in growth arrest, cellular differentiation, and apoptosis. is an anti-CD52 antibody that is approved for chronic lymphoid leukemia treatment. It has been showed that it Two of these agents (vorinostat and romidepsin) have is effective on T-cell prolymphocytic leukemia with high been approved in the USA for the treatment of relapsed and response rate in a prospective study including 39 patients refractory CTCL. In these studies, they have been used as a with T-PLL treated with CAMPATH-1H [32]. The overall single agent. Studies are ongoing to evaluate their efficacy on response rate was 76% with 60% CR and 16% partial PTCL. remission (PR). These responses were durable with a median Vorinostat was evaluated in a phase II study. This study disease-free interval of 7 months (range, 4–45 months). included 74 pts with CTCL who had failed at least two In ATL, experience is limited to case report [33]. In prior systemic therapies [28]. The primary end point was addition, a recent study reported efficacy of the association overall response rate (ORR). ORR was 29.7%. Median time of alemtuzumab and pentostatin in various types of PTCL to objective response was 56 days (range, 28–171). Median including one case of ATL, which was in CR [34]. However, duration of response was not reached but estimated to be association Campath with conventional chemotherapy in more than 185 days (range, 34–441). Major side effects were PTCL has shown relative efficacy but high rate of infections. diarrhea (49%), fatigue (46%), nausea (43%), and anorexia (26%). Eleven patients required dose modification and nine discontinued due to adverse event. On the basis of this study, 9.4. Lenalidomide. Lenalidomide is a drug currently used the U.S. FDA approved Vorinostat for CTCL in October of for myeloma treatment. Studies have reported its use as 2006. single therapy for PTCL treatment. An interim report for a phase 2 clinical trial has been reported [35]. Patients Romidepsin was the second HDAC inhibitor that was with recurrent and refractory T-cell lymphomas other than approved by the U.S. FDA for CTCL in 2009. Two phase mycosis fungoides and untreated patients ineligible for com- 2 trials were conducted in patients with CTCL with the primary goal of determining response rate and tolerance bination chemotherapy were prescribed oral lenalidomide (25 mg daily) on Days 1 to 21 of each 28-day cycle until toxicity profile. The first trial included 71, and 96 patients were treated on a second trial. Response rates were 34% for disease progression. At the time of this interim analysis, 24 patients were enrolled in this study, and 23 were evaluable both studies with median durations of 13.7 and 15.4 months, respectively, [29]. Side effects that were acceptable included for response. The overall response rate was 7 (30%) of nausea, vomiting, fatigue, and transient thrombocytopenia 23; all were in partial responses. Two patients had stable and granulocytopenia. Romidepsin was approved for CTCL disease for ≥5 cycles. Median PFS was 96 days (range, 8– after these two studies. 696 days). Median OS was 241 days (range, 8–696 days). The Leukemia Research and Treatment 5 most common grade 4 adverse event was thrombocytopenia chemotherapy should be the preferred option. However, (33%). recent unpublished results from the UK suggest that com- bination of antiviral therapy with CHOP chemotherapy is superior to CHOP alone in patients with ATL lymphoma 9.5. Bendamustine. Bendamustine is a cytotoxic agent that [36]. Use of chemotherapy is based on the Japanese expe- has been recently approved for the treatment of CLL and rience across different trials. The LSG15 protocol is the indolent lymphoma such as follicular lymphoma. This “standard of care.” It is based on multiple drugs. When drug shows structural similarities with alkylating agents or treated with this LSG15 protocol, ATL lymphoma patients antimetabolites. A phase II study tests his efficacy on relapsed achieved a better CR rate (66.7%) than acute type (19.6%) or refractory peripheral T-cell lymphoma. The primary end or chronic type (40.0%). However, relapse occurs rapidly point is ORR (CR, CRu, PR). Preliminary results have been and overall survival rate is low [6]. Therefore, a consolida- shown recently for the first 38 patients (G. Damaj et al. 11th tion therapy is critical. Whenever possible, allogeneic SCT International Conference on Malignant Lymphoma, abstract should be considered [8]. For patient failing to achieve n 126). ORR was 47%: CR + CRu in 11 patients (29%), PR remission after chemotherapy or lacking a suitable donor, in 7 patients (18%). 20 patients experienced relapse. At the a consolidation strategy should be discussed. Based on time of analysis, the median duration time for responder preclinical data, ongoing clinical trials are testing the efficacy patients was 157 days (range, 14–350). The most adverse of two cycles of arsenic/IFN maintenance as a consolidation events (grade 3 and 4) were neutropenia and thrombopenia. procedure following achievement of CR with encouraging preliminary results [22]. Moreover, the addition of AZT/IFN 10. Strategy or other novel therapies to chemotherapy may help to achieve remission. HDAC inhibitor might be tested in this Suggested treatment strategies according to clinical presenta- indication to induce an immune response against residual tion are described in Figure 1. tumor cells. 10.1. Chronic and Smoldering ATL. Patients with chronic and smoldering ATL have a better prognosis compared to patients 10.3. Acute ATL. Combination chemotherapy regimens have with aggressive forms (acute and lymphoma). However, as little effect in acute ATL. Even if the most intensive regimen it has been shown in a recent Japanese study, long-term (LSG-15) have increased response rate, MST and OS are low survival is dismal when these patients are managed with a [6, 7]. In the recently published meta-analysis on antiviral watchful-waiting policy until disease progression. Moreover, therapy for ATL, treatment of acute ATL patients with AZT patients who received chemotherapy alone had a poorer and IFN showed a higher response rate and significantly outcome indicating that this may be detrimental in these prolonged survival. Moreover, patients who achieved CR subtypes [3]. So far, no clear prognostic factors have been yet had a long-term response [16]. Outside the context of defined in order to predict transformation to an aggressive clinical trials, the current standard therapy of acute ATL is form and treated patient who are at risk. combination therapy with AZT and IFN. However, it can Our point of view is that most of patients with chronic be difficult to manage patients presenting with bulky tumor and smoldering ATL should be treated. In the recent or severe hypercalcemia not responding to bisphopshonates, worldwide meta-analysis, patients with chronic/smoldering and initial chemotherapy is sometimes required. It would ATL who received first-line therapy by AZT-IFN only had an be helpful to predict which patients in the acute form excellent survival (100% OS beyond 5 years). Thus, outside will benefit from this approach. Preliminary results indicate the context of clinical trials, the current standard therapy of that patients with wild-type functional p53 are more likely chronic and smoldering ATL is combination therapy with to respond to AZT/IFN combination [37]. We, therefore, AZT and IFN. This requires, however, continuous therapy. recommend evaluating p53 by a functional assay in all Treatment should not be interrupted as relapse always occurs patients while the treatment is initiated [38]. Long-term when treatment is stopped. The recommended starting disease control requires, however, continuous therapy, since dose is AZT 600 to 900 mg/day (in 3 divided doses) and relapse is always noted when treatment is stopped. The interferon-alpha (5 to 6 million IU/m2/day). Usually, after recommended dose is the same as with chronic/smoldering one month, AZT dose can be titrated down to 600 mg/day form.Asinlymphomasubtype,allogeneicHSCTshould in 2 divided doses and IFN dose can be reduced to 3 to 5 be considered for young patients with acute ATL and a million IU/day or alternatively 1.5 μg/kg of pegylated IFN suitable donor [38]. As in other ATL subtype, based on weekly. Based on preclinical studies, clinical trials are testing preclinical data, ongoing clinical trials are testing the efficacy the effect of adding arsenic to the AZT/IFN combination as a of arsenic/IFN maintenance following achievement of CR. consolidation therapy with the aim of then stopping therapy and achieving cure by potential elimination of leukaemia- 10.4. Supportive Therapy in ATL. Hypercalcaemia associated intiating cells [17–20]. with aggressive ATL should be managed with treatment of the disease, hydration, and bisphosphonate therapy. 10.2. ATL Lymphoma. As has been shown in the recent meta- Trimethoprim-sulfamethoxazole, valacyclovir, and antifun- analysis, the combination AZT-IFN is less effective than gal agents are recommended for the prophylaxis of Pneumo- first-line chemotherapy in ATL lymphoma [16]. Therefore, cystis jiroveci pneumonia, herpes simplex virus, and fungal 6 Leukemia Research and Treatment Induction therapy Maintenance IFN-AZT Smoldering/ IFN-AZT Addition of trioxide arsenic to eradicate MRD chronic or HDAC inhibitor (to be tested in clinical trials) Chemotherapy alloSCT if feasible ATL lymphoma LSG 15 protocol IFN-AZT intrathecal chemotherapy Addition of trioxide arsenic to eradicate MRD IFN-AZT CR Addition of trioxide arsenic to eradicate MRD IFN-AZT Response ATL acute intrathecal chemotherapy alloSCT if feasible at 2 months P53 screening No CR Clinical trials testing new drugs Figure 1: Recommended treatment strategy for patients with acute, lymphoma, or chronic/smoldering ATL (CR: complete remission; MRD: minimal residual disease; AZT: zidovudine; IFN: interferon-alpha; alloSCT: allogeneic stem cell transplantation). infections, respectively; in the Japanese Trials, prophylaxis regimen but constantly relapse and have a poor prognosis. with antistrongyloides agents, such as ivermectin or alben- Addition of AZT-IFN in combination with chemotherapy dazole, should be considered in order to avoid systemic may increase response rate but its long-term effect remains infection in patients with a history of past and/or present to be determined. We recommend, for those in whom exposure to the parasite. Intrathecal prophylaxis should be alloSCT is not feasible, that a consolidation treatment with considered for patients with aggressive ATL even in the AsO is considered, followed by maintenance therapy with absence of clinical symptoms because more than half of AZT/IFN. This approach should be tested in future clinical relapses at new site after chemotherapy occur in the central trials. Prophylaxis of opportunistic infections and supportive nervous system. therapy are mandatory. In order to prevent the occurrence of resistance and relapse, clinical trials assessing additional targeted therapies such as arsenic/IFN combination or 11. Conclusion monoclonal antibodies, particularly the promising anti- The combination of AZT and IFN is highly effective in CCR4 antibodies, are mandatory after achieving CR. Finally, the leukemic subtypes of ATL and should be considered as allogeneic SCT should be considered in suitable patients. standard in first-line therapy in that setting. This combina- HDAC inhibitor may be also an interesting option. Currently, tion has clearly changed the natural history of the disease due to the poor outcome of patients with aggressive ATL through achievement of a significantly improved long-term (acute and lymphoma forms), phase II studies are mandatory survival in patients with smoldering and chronic ATL as in the near future. In chronic form, it is time to set up phase well as a subset of patients with acute ATL. Prior exposure III studies to assess new drugs to avoid relapse for patients to chemotherapy increases the rate of complications and of treated with AZT-IFN. acquiring p53 mutations. 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