Regimens In Younger Patients Research Articles

Advancements and Challenges in the Treatment of AML.

The therapeutic arsenal for the management of AML has expanded significantly in recent years. Before 2017, newly diagnosed AML was treated with either standard cytarabine- and anthracycline-based induction chemotherapy (for all fit patients) or a single-agent hypomethylating agent (in unfit patients or those 75 years and older). While assessing patient fitness remains important, characterizing the disease biology has become critical to select the optimal initial therapy for each patient with more options available. FLT3 inhibitors, gemtuzumab ozogamicin, and CPX-351 have been shown to improve outcomes for specific subsets of patients. Venetoclax (VEN) with a hypomethylating agent (HMA) is the standard-of-care frontline regimen for most older patients, except perhaps for those with an IDH1 mutation where ivosidenib with azacitidine may also be considered. On the basis of the success seen with HMA/VEN in older patients, there is now increasing interest in incorporating VEN into frontline regimens in younger patients, with promising data from multiple early phase studies. This article focuses on recent updates and ongoing challenges in the management of AML, with a particular focus on the ongoing challenge of secondary AML and considerations regarding the selection of initial therapy in younger patients. An overview of common side effects and toxicities associated with targeted therapies is also presented here, along with recommended strategies to mitigate these risks.

The Optimal Busulfan Dose of Conditioning Regimens for Allogeneic Hematopoietic Cell Transplantation in Younger Patients with Acute Myeloid Leukemia

Background: In allogeneic hematopoietic cell transplantation (HCT) for younger patients with acute myeloid leukemia (AML), myeloablative conditioning (MAC) regimens have been considered as standard conditioning. MAC can reduce the risk of relapse, but increase non-relapse mortality, including organ toxicity and severe graft versus host disease. Therefore, the optimal busulfan dose in conditioning regimens has not been established in younger patients with AML. Thus, we aimed to investigate post-HCT outcomes according to the busulfan dose of conditioning regimens in younger patients with AML. Methods: We retrospectively analyzed long-term outcomes according to the busulfan dose (2 days vs. 3 days vs. 4 days) in 686 adult patients (age <55 years) with AML who had undergone HCT between 2000 and 2020 at the Asan Medical Center, Seoul, Korea. The clinical data was collected from the Asan Medical Center HCT registry. Patients with AML who had undergone a second or third HCT were excluded from this study. Results: The median age was 41 (range 15-54). The 5-year overall survival (OS) and event-free survival (EFS) rate was 52.2% and 46.4%, respectively. The 3 days of busulfan (Bu3) (n=88) showed significantly higher OS than 4 days of busulfan (Bu4) (n=229) and 2 days of busulfan (Bu2) (n=369) (2-year OS; 76.1% vs. 65.1% and 56.3%, respectively; P<0.001). The EFS rate of Bu3 and Bu4 was significantly higher than that of Bu2 (2-year EFS; 60.2% and 59.8% vs. 46.9%, respectively; P<0.001). Among the three groups, there was no significant difference in GRFS (P=0.952). The cumulative incidence of relapse was significantly lower in Bu4 (26.2% at 2 years) than in Bu2 (40.4%) and Bu3 (36.4%) (P<0.001). However, the NRM was significantly higher in Bu4 (13.9% at 2 years) and Bu2 (12.7%) than in Bu3 (3.4%) (P=0.005). In HCT at complete remission (CR) status, Bu3 showed significantly better OS than Bu4 and Bu2 (P=0.039), whereas there was no significant difference in EFS according to the busulfan dose (P=0.121). In patients with refractory disease, however, the higher dose of busulfan (Bu3 or Bu4) did not show survival advantages in terms of OS (P=0.153) and EFS (P=0.829) over Bu2. Regarding donor types, Bu3 showed significantly better OS than Bu2 in HCT from matched sibling donors (MSD) (P=0.030) and haploidentical family donors (HFD) (P<0.001). However, in HCT from unrelated donors (URD), the Bu2 group showed the best GRFS, and OS in Bu2 or Bu3 was significantly longer than in Bu4 (P=0.028). Conclusion: For younger patients with AML, Bu3 would be the optimal conditioning intensity in HCT from MSD or HFD at CR status. In URD, Bu2 or Bu3 would be appropriate. In refractory disease, increasing busulfan dose intensity could not improve post-HCT outcomes.

Comparison of a Combination of Vosaroxin (VOS) and Intermediate-Dose Cytarabine (IDAC) with Idac for the Consolidation Therapy of Younger Patients with Favorable- and Intermediate-Risk Acute Myeloid Leukemia (AML) in First Complete Remission (CR): Preliminary Results of a Randomized Phase 2 R4-VOS Study of the French ALFA-Filo AML Intergroup

Comparison of a Combination of Vosaroxin (VOS) and Intermediate-Dose Cytarabine (IDAC) with Idac for the Consolidation Therapy of Younger Patients with Favorable- and Intermediate-Risk Acute Myeloid Leukemia (AML) in First Complete Remission (CR): Preliminary Results of a Randomized Phase 2 R4-VOS Study of the French ALFA-Filo AML Intergroup

OS08.8 A head-to-head comparison of two different high dose methotrexate (HDMTX) - and high dose cytarabin (HDAraC)-based chemotherapy regimens in younger patients with primary central nervous system lymphoma (PCNSL)

OS08.8 A head-to-head comparison of two different high dose methotrexate (HDMTX) - and high dose cytarabin (HDAraC)-based chemotherapy regimens in younger patients with primary central nervous system lymphoma (PCNSL)

Development of a physiologically based pharmacokinetic model of actinomycin D in children with cancer.

AimsUse of the anti‐tumour antibiotic actinomycin D is associated with development of hepatotoxicity, particularly in young children. A paucity of actinomycin D pharmacokinetic data make it challenging to develop a sound rationale for defining dosing regimens in younger patients. The study aim was to develop a physiologically based pharmacokinetic (PBPK) model using a combination of data from the literature and generated from experimental analyses.MethodsAssays to determine actinomycin D Log P, blood:plasma partition ratio and ABCB1 kinetics were conducted. These data were combined with physiochemical properties sourced from the literature to generate a compound file for use within the modelling‐simulation software Simcyp (version 14 release 1). For simulation, information was taken from two datasets, one from 117 patients under the age of 21 and one from 20 patients aged 16–48.ResultsThe final model incorporated clinical renal and biliary clearance data and an additional systemic clearance value. The mean AUC0‐26h of simulated subjects was within 1.25‐fold of the observed AUC0‐26h (84 ng h ml−1 simulated vs. 93 ng h ml−1 observed). For the younger age ranges, AUC predictions were within two‐fold of observed values, with simulated data from six of the eight age/dose ranges falling within 15% of observed data. Simulated values for actinomycin D AUC0‐26h and clearance in infants aged 0–12 months ranged from 104 to 115 ng h ml−1 and 3.5–3.8 l h−1, respectively.ConclusionsThe model has potential utility for prediction of actinomycin D exposure in younger patients and may help guide future dosing. However, additional independent data from neonates and infants is needed for further validation. Physiological differences between paediatric cancer patients and healthy children also need to be further characterized and incorporated into PBPK models.

Clinical Presentation and Outcome of ABVD-Treated Elderly Versus Younger Patients with Classical Hodgkin´s Lymphoma

BackgroundApproximately 20% of classical Hodgkin’s Lymphoma (cHL) patients are over 60 years of age. There is no standard of care for this age group. Although most patients receive ABVD (Doxorubicin, bleomycin, vinblastine and dacarbazine), a standard regimen in younger patients, little is known regarding the clinical presentation of cHL, and the long term efficacy of ABVD in young and elderly Latin American Mestizo patients.. Defining whether individuals in all age groups and social circumstances benefit from a common treatment approach requires investigation..Thus we sought to evaluate and compare the clinical presentation and the efficacy of ABVD in the elderly (60 years of age and above) versus the younger population of individuals with cHD.MethodsWe retrospectively analyzed 44 consecutive cHL patients treated with ABVD at the National Cancer Institute in Mexico between 2006 and 2013, as compared to 218 patients under 60 years of age.ResultsMedian age for the elderly was 65 (60-89y), without a difference in gender (21m/2 f). According to Ann Arbor staging 6-8-13-14 were stage I, II, III, or IV , respectively. The International Prognostic Score (IPS) was > 3 in all patients. B symptoms were present in 34 patients (77.3%). Mixed cellularity subtype was present in 52.3% of cases and nodular sclerosis subtype (34.1%). The great majority of patients (93%) received at least 1 ABVD (1-6), 27 patients received chemotherapy alone, 14 patients received combined modality treatment and 3 patients only received radiotherapy. Twenty four patients achieved a CR (54.5%), 5 partial responses, 5 had refractory /relapsed disease and 10 couldn’t be evaluated. Unlike younger patients a better response was not demonstrated with combined treatment modality (Table 1). Overall survival for the whole group at 7.2 years was estimated at 75.4% (95% CI 57.1-79.4) The OS (7 y) in elderly group was 75% versus 92% in younger group, however patients with age >75 had a lower survival, 50%. The median follow-up was of 8 years.SummaryOur study showed no clinical differences between elderly vs younger population and confirms the efficacy of ABVD in elderly patients. The lower OS compared to other series may be related to the advanced stage of disease and poor IPS in our series Table 1Clinical characteristics of elderly versus younger patientsFeature< 60 years (%)>60 years (%)P valueGenderMale/female61.8/38.247.5/52.30.10B Symptoms77.077.30.86Ann Arbor stageIIIIIIIV7.424.931.835.913.618.224.538.60.45IPS >348.865.90.07Bulky disease48.838.60.26HistologyMixed cellularityNodular Sclerosis43.848.852.334.10.60TreatmentABVDABVD + RTRTOther42.455.32.32.361.431.86.84.50.37ResponseCRPRRelapse/progressionNV60.89.718.910.654.511.411.422.70.37Overall survival (8 years)92%75%0.000 DisclosuresNo relevant conflicts of interest to declare.

Mantle Cell Lymphoma: Taking Therapeutic Advantage of New Insights into the Biology

Mantle cell lymphoma (MCL) is an uncommon, incurable B-cell non-Hodgkin's lymphoma that afflicts the elderly. There is no standard course of treatment, with options varying from observation in asymptomatic patients to aggressive induction/consolidation regimens in younger patients with rapidly progressive disease. Emerging data regarding the role of the ubiquitin-proteasome system, B-cell receptor and mTOR signaling pathways, cell cycle regulation, and epigenetic and immune-modulation in the pathogenesis of MCL have resulted in the development of novel therapies, with a shift away from conventional cytotoxic chemotherapy to relatively less toxic, more targeted treatment. The challenge now is to determine the optimal sequence and combination of the various available and emerging therapies for use in patients with MCL.

Role of Ibrutinib for the Treatment of Mantle Cell Lymphoma in the Elderly

SUMMARY Mantle cell lymphoma (MCL) is an uncommon, incurable B-cell non-Hodgkin lymphoma that primarily occurs in the elderly. There is no standard management of MCL, with options varying from observation in asymptomatic patients to aggressive induction/consolidation regimens in younger patients with rapidly progressive disease. Ibrutinib is a first-in-class covalent inhibitor of Bruton’s tyrosine kinase and has shown clinical activity in several B-cell lymphomas including MCL. It is taken orally once daily and appears to be well tolerated. Based on promising results from a Phase II clinical trial in MCL, ibrutinib received breakthrough therapy designation and was approved by the US FDA for treatment of patients with MCL that have received at least one prior line of therapy. It is undergoing further testing in the front line and relapsed setting.

Biology and Outcome of 85 Adults with Acute Lymphoblastic Leukemia (ALL) with t(4;11)/MLL-AF4 Treated in the UKALL XII/ECOG 2993 Study

AbstractAbstract 663 Introduction:The biology and outcome of adult t(4;11) ALL are poorly understood. We report here 85 patients treated uniformly on the prospective trial (UKALL XII/ECOG 2993) with the aim of describing outcome and identifying prognostic factors and optimal therapy. Patients and methods:1914 adult patients (≥15 years) with ALL were registered on the UKALL XII/ECOG 2993 study in the UK or United States from 1993–2006. Cell lineage was classified by local institutions (UK) or central immunophenotyping (ECOG). Cytogenetic, FISH and RT-PCR analyses of pre-treatment samples were either performed locally and reviewed centrally or performed centrally. Results:The 85 patients with t(4;11) were predominantly female (68%). Median age was 38 years (vs 32 years in the non-t(4;11) group) and 42% were >40 years. They had high white cell counts with 87% >30 and 66% >100 × 109/l (vs 7% in the non-t(4;11) group).Among the 27 ECOG patients, 22 (81%) had the typical pro-B (CD10NEG) immunophenotype, compared to 12% in t(4;11)NEG patients. Aside from expression of myeloid antigens, CD65 and CD15, which is part of the pro-B immunophenotype, t(4;11)POS lymphoblasts showed a unique combination of stem cell antigens: lower expression of CD34 and CD105, but higher expression of CD133 and CD135 compared to t(4;11)NEG blasts (p<0.0001).Additional cytogenetic abnormalities (ACAs) were present in 31/75 (41%) evaluable cases. Most common ACAs were gain of chromosome X (n=13), i(7)(q10) (n=7) and abnormalities of 1p (n=4). Deletion of IKZF1 or CDKN2A/B was present in 18% of patients tested; neither affected outcome.Seventy seven evaluable patients attained complete remission (CR1, 93%). Treatment received in CR1 was either chemotherapy (n=46, 59%) or a myeloablative allograft (N=31, 16 matched sibling, 1 mismatched related and 15 unrelated donors UD). CR1 treatment received strongly correlated with age with the number of allografts decreasing with age: <25 years 12/17 patients; 24–39 years 13/29 and 40+ years 6/31 (p=0.001).At median follow up of 5.4 years, five year EFS was 34% (24–44%, 95% CI) and OS 35% (25–45%). Five year relapse rate was 45% (33–58%); only 1 relapsed patient survived, nearly all events had occurred by 2 years. The 46 patients who received chemotherapy had 24% survival and 69% relapsed but 5 year OS of patients who had sibling or UD allografts was 56% and 67% respectively (p=0.013) and only 3/31 relapsed. An allograft improved OS, EFS and relapse in the <40 year group. Age was also strongly associated with outcome (figure). Conclusions:This is the largest series of adult t(4;11) ALL patients treated uniformly. Allograft in CR1 from sibling or unrelated donors is an effective strategy. Current prospective trials of intensive pediatric-type regimens in younger patients will determine if CR1 allografts are necessary. Older patients have a poor outcome and different strategies such as reduced intensity allografting should be explored. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The Addition of Rituximab to Fludarabine and Cyclophosphamide Improves Progression-free Survival in Patients with Previously Treated Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States [1]. There has been considerable progress in understanding the biology and treatment of CLL in last 20 years. The introduction of purine analogs (pentostatin, fludarabine, and cladribine) dramatically increased the response rates compared to alkylating agents [2, 3]. Combination chemoimmunotherapy has further improved the overall frequency of response to over 80% in treatment-naive and over 60% in relapsed/ refractory disease, respectively [4–7]. The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has been demonstrated to be one of the most effective regimens in younger patients with CLL in phase 2 trials. Tam et al. [4], reporting on 300 patients, noted an overall response frequency of 95% with 72% achieving complete response (CR) in patients treated with FCR as initial therapy for CLL. Other studies of FCR, reported by Lamanna et al. [7] and Foon et al. [8], revealed an overall response frequency of 100% and 89%, respectively, with CR in 77% and 61% of patients, respectively. In the salvage setting, FCR achieved a CR in 25% and overall response in 73% of the patients [5]. However, none of the prior studies have directly compared the addition of rituximab to fludarabine and cyclophosphamide in previously treated patients with CLL. Robak and colleagues report on a phase 3 trial, conducted at 88 centers in 17 countries between July 2003 and August 2007, that randomized previously treated patients with CLL to FC or FCR.

Le lymphome à cellules du manteau : du diagnostic aux perspectives thérapeutiques

Mantle cell lymphoma (MCL) is a rare non-Hodgkin lymphoma (NHL) entity. The translocation between chromosomes 11 and 14 is the cytogenetics hallmark of MCL. This translocation leads to the dysregulation of the CCDN1 gene, and overexpression of cyclin D1 which promotes cell cycling. Despite a classical phenotype (CD19+, CD20+, CD5+, CCND1+, CD10-, CD23-, Bcl-2+, Ig at the membrane, mainly IgM), MCL is not a homogeneous disease and several cytological, phenotypic, cytogenetic and clinical variants have been described. MCL represents 5 % of NHLs with its incidence constantly increasing over the last years. Median age at diagnosis is 68 years. Stage III-IV disease is observed in more than 80 % of patients at presentation, with intestinal and bone marrow being the most frequently involved organs, while the spleen is enlarged in half of cases. Intensive strategies including high-dose chemotherapy, followed by autologous stem cell transplantation have significantly improved the outcome of MCL patients. Median overall survival rate increased from 3 to 5 years during the last decade. At present, induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard regimen in younger patients. However, most of MCL patients will experience relapse. Thus, close monitoring of minimal residual disease (currently under evaluation) may represent a valuable tool for assessment of disease response during follow-up. Future innovative therapies that are being presently investigated in prospective trials include transduction pathways inhibitors, proteasome inhibitors, pro-apoptotic molecules, immunotherapy and/or radiolabeled immunotherapy, and will likely open a new era for targeted therapies in MCL.

Alternating Bortezomib and Dexamethasone as Induction Regimen Prior to Autologous Stem-Cell Transplantation in Newly Diagnosed Younger Patients with Multiple Myeloma: Results of a PETHEMA Phase II Trial.

Dexamethasone-based combinations have been the standard induction regimens in younger patients with multiple myeloma (MM) prior to stem cell transplantation. Bortezomib alone or in association with dexamethasone has shown significant activity in patients with both refractory/relapsed and newly diagnosed MM. We investigated the efficacy of bortezomib and dexamethasone administered on an alternating basis, the end-points of the study being response rate, kinetics of response, safety, stem cell mobilization and response postransplant. Patients with newly diagnosed MM under the age of 66 years and with adequate organ and function status were eligible. Patients were treated with bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 (cycles 1, 3, 5) and dexamethasone 40 mg p.o. on days 1–4, 9–12 and 17–20 (cycles 2, 4 and 6), followed by high dose-therapy intensification (HDT) with melphalan -200. Responses were evaluated by the EBMT criteria but a near-CR (n-CR) response category was included. Stem cell mobilization was performed after G-CSF priming. Between August, 2005 and March, 2006, 40 patients (18 M, 22F, median age 57 yrs) were enrolled. The M-protein type was IgG in 26 patients, IgA in 11 and light chain in 3. Six patients had extramedullary plasmacytomas. At the time of this analysis response data after the 6 cycles were available for 26 of the 40 patients. The overall response rate was 76% and the CR rate 15% (4 CR, 5 n-CR, 7 PR, 4 MR, 2 stable disease, 3 progressive disease, 1 non-evaluable because of treatment discontinuation due to toxicity after cycle 1). In patients who achieved at least PR the mean M-protein decrease was 84% (48% associated with bortezomib cycles and 36% with dexamethasone). Two responding patients showed disease progression immediately before HDT. In all thirteen patients mobilized to date stem cells could be adequately collected (median CD34+ cells: 4.85 x106/Kg; range 2–10.6) with only one apheresis. Toxicity was low and mainly consisted of grade 1 and 2 neutropenia, fever, GI symptoms, fatigue, peripheral neuropathy and thrombocytopenia. Ten (25%) patients developed mild peripheral neuropathy (grade 1=9 cases; grade 2=1 case) and 11 patients grade 1 thrombocytopenia. Grade 3 toxicity was only observed in 7 patients (neutropenia 6, skin/liver 1 case) and no patient developed grade 4 toxicity. Updated results on all patients along with cytogenetic data will be presented at the meeting. In conclusion, bortezomib alternating with dexamethasone is highly effective as up-front therapy in patients with MM, is associated with an extremely low toxicity and results in an excellent stem cell harvesting. The results of this trial support a short program of alternating bortezomib and dexamethasone as an effective and safe induction regimen for newly diagnosed younger myeloma patients.

Due to low infection rates no routine anti‐infective prophylaxis is required in younger patients with chronic lymphocytic leukaemia during fludarabine‐based first line therapy

The impact of the combination therapy fludarabine plus cyclophosphamide (FC) in comparison with fludarabine alone regarding the incidence and severity of infections among previously untreated patients with chronic lymphocytic leukaemia (CLL) was evaluated within a multicentre phase III study. A total of 375 patients, up to 65 years old, were randomised between fludarabine or FC for first line therapy. No routine anti-infective prophylaxis was provided. A total of 196 infectious episodes, including 33 severe infections, were documented. In the fludarabine arm, 32.9% of the patients developed an infectious complication compared with 39.9% in the FC arm (P = 0.2). No difference was observed in the rate of severe infections (Common Toxicity Criteria grades III and IV) between both treatment arms. Dose reductions were performed more frequently in FC-treated patients. Granulocyte colony-stimulating factor (G-CSF) was administered due to leucopenia in 5% of all patients. A multivariate regression model identified only elevated thymidine kinase, but not the treatment arm, as a statistically independent risk factor for infections. In summary, FC was not associated with a higher rate of infections compared with fludarabine alone. No routine antibiotic or virostatic prophylaxis, or preemptive treatment with G-CSF, is necessary in first line therapy with fludarabine-based regimens in younger patients with CLL, if adequate dose reduction is performed. The combination therapy FC is not associated with a higher rate of infections compared with fludarabine alone. No routine antibiotic or virostatic prophylaxis as well as preemptive treatment with G-CSF is necessary in first line therapy with fludarabine-based regimen in younger patients with CLL, if adequate dose reductions due to cytopenia or previous infections are performed.

Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation.

In this study, we evaluated the influence of nonmyeloablative and ablative conditioning regimens on the occurrence of acute and chronic graft-versus-host disease (GVHD). One hundred thirty-seven patients undergoing matched-related sibling transplantations received the same GVHD prophylaxis. Myeloablative regimens included intravenous busulfan/cyclophosphamide (n=45) and fludarabine/melphalan (n=29). Patients in the nonmyeloablative group (n=63) received fludarabine/idarubicin/cytarabine, cisplatin/fludarabine/idarubicin, and fludarabine/cyclophosphamide. The actuarial rate of grade II to IV acute GVHD was significantly higher (hazard ratio, 3.6; 95% confidence interval, 1.5-8.8) in patients receiving ablative regimens (36%) compared with the nonmyeloablative group (12%). The cumulative incidence of chronic GVHD was higher in the ablative group (40%) compared with the nonmyeloablative group (14%). The rates were comparable within the first 200 days and were significantly higher in the ablative group beyond day 200 (hazard ratio, 5.2; 95% confidence interval, 1.2-23.2). Nonrelapse and GVHD-related mortality were relatively low in both groups. The use of the described nonmyeloablative preparative regimens was associated with a reduced incidence of grade II to IV acute GVHD and chronic GVHD compared with the busulfan/cyclophosphamide and fludarabine/melphalan transplant regimens. It is interesting to note that nonrelapse mortality with nonmyeloablative regimens in older and more debilitated patients was low (14%) and comparable to that achieved with standard high-dose regimens in younger patients.

Bone marrow transplantation in adult thalassemia

Early trials of allogeneic marrow transplantation for homozygous thalassemia were disappointing in patients older than 16, with four of six patients dying early of graft-versus-host disease-related complications, one patient dying at 9 months of infection due to graft failure, and one dying at 6 years of recurrent thalassemia. Three classes of risk could be identified in analyses of results of transplantation in younger patients using the criteria of degree of hepatomegaly, the presence or absence of portal fibrosis, and a history of adequate or inadequate chelation therapy. Patients for whom all three criteria were adverse constituted a very high risk group (class 3) for marrow transplantation. On the basis of these analyses, a conditioning regimen was designed that yielded superior results for class 3 patients under 17 years of age. Most patients older than 16 years presenting for transplantation have disease characteristics that place them in class 3 and, because of the improved results with the new class 3 regimen in younger patients, a study was designed to treat patients older than 16 years using treatment regimens assigned on the basis of disease class. Twenty patients were treated using this protocol and, with a minimum follow-up of 9 months, there have been three early deaths, one patient has recurrent thalassemia, and 16 patients are alive disease-free. The actuarial probabilities of survival, disease-free survival, and rejection are 0.85, 0.80, and 0.05, respectively, with a survival plateau extending from 6 months to 3 years. Marrow transplantation is a reasonable option for adults with progressive thalassemia who have suitable donors.

Bone Marrow Transplantation in Adult Thalassemia

Early trials of allogeneic marrow transplantation for homozygous thalassemia were disappointing in patients older than 16, with four of six patients dying early of graft-versus-host disease-related complications, one patient dying at 9 months of infection due to graft failure, and one dying at 6 years of recurrent thalassemia. Three classes of risk could be identified in analyses of results of transplantation in younger patients using the criteria of degree of hepatomegaly, the presence or absence of portal fibrosis, and a history of adequate or inadequate chelation therapy. Patients for whom all three criteria were adverse constituted a very high risk group (class 3) for marrow transplantation. On the basis of these analyses, a conditioning regimen was designed that yielded superior results for class 3 patients under 17 years of age. Most patients older than 16 years presenting for transplantation have disease characteristics that place them in class 3 and, because of the improved results with the new class 3 regimen in younger patients, a study was designed to treat patients older than 16 years using treatment regimens assigned on the basis of disease class. Twenty patients were treated using this protocol and, with a minimum follow-up of 9 months, there have been three early deaths, one patient has recurrent thalassemia, and 16 patients are alive disease-free. The actuarial probabilities of survival, disease-free survival, and rejection are 0.85, 0.80, and 0.05, respectively, with a survival plateau extending from 6 months to 3 years. Marrow transplantation is a reasonable option for adults with progressive thalassemia who have suitable donors.