Candidates For Experimental Therapies Research Articles

Abstract CT126: An open-label, first-in-human study of BAY2927088 in patients with advanced non-small cell lung cancer (NSCLC) harboring an EGFR and/or HER2 mutation

Abstract Background: Despite targeted agents recently approved for treating patients with advanced NSCLC harboring EGFR exon 20 insertion (ex20ins) mutations, there is still a high unmet need for more effective agents with good tolerability. BAY2927088 is an oral, reversible, highly potent TKI targeting EGFR and HER2 driver mutations with high selectivity for ex20ins vs wild-type EGFR. In addition, BAY2927088 retains potent antiproliferative activity in the presence of EGFR C797S acquired resistance (AR) mutation due to its non-covalent binding mode. In preclinical studies, BAY2927088 demonstrated strong dose-dependent in vivo tumor growth inhibition in NSCLC EGFR ex20ins mutant patient-derived xenograft models and models carrying the AR mutation C797S (Siegel et al, ENA 2022). The strong potency and high selectivity of BAY2927088 for mutant vs wild-type EGFR offers the prospect of an improved therapeutic window in the clinical setting vs available EGFR TKIs. Methods: 21607 is an open-label, multicenter, first-in-human Phase I study of BAY2927088 in patients with advanced NSCLC harboring EGFR or HER2 mutations. The study comprises dose escalation, backfill, and dose expansion. The dose escalation is enrolling patients with EGFR or HER2 driver mutations and follows a modified continual reassessment method, allowing for concurrent backfill to previously cleared dose levels that demonstrated therapeutically relevant exposures or direct evidence of clinical activity in patients harboring ex20ins or EGFR C797S mutations. Dose-limiting toxicities are evaluated for 21 days. The primary objective of dose escalation is to determine BAY2927088 safety, tolerability, PK, and maximum tolerated dose. Dose expansion will enroll patients based on specific EGFR/HER2 mutations and previous treatment, including those with ex20ins mutation either naïve or pretreated with ex20ins-targeted agents and those with AR EGFR C797S mutation. Key objectives of dose expansion are to further characterize BAY2927088 safety, tolerability, and to characterize PK of the optimal dose(s) selected during dose escalation and backfill. Key secondary objectives include determining antitumor activity based on overall response rate per RECIST v1.1 and the recommended Phase II dose of BAY2927088. Eligible patients must have measurable disease per RECIST v1.1, have a documented EGFR or HER2 mutation in tumor tissue or plasma, have disease progression after treatment with ≥1 systemic therapy for advanced disease, be appropriate candidates for experimental therapy, be aged ≥18 years, have ECOG PS of 0 or 1, and have adequate organ function. Key exclusion criteria include presence of serious cardiac conditions, interstitial lung disease, active CNS metastasis, or leptomeningeal disease. The trial is currently enrolling patients in dose-escalation and backfill parts (NCT05099172). Citation Format: Daniel Tan, Koichi Goto, Herbert HF Loong, Tsung-Ying Yang, Shirish Gadgeel, Erminia Massarelli, Gennaro Daniele, Xiuning Le, Yuki Shinno, Haruyasu Murakami, Tomohiro Sakamoto, Jose C. Ruffinelli, Shun Lu, Yiping Zhang, Tae Min Kim, Barbara J. Brennan, Chunlin Chen, Miranda Joosten, Zebin Wang, Su-Fen Pu, Weichao Bao, Martin Kornacker, Roberta Ferraldeschi, Paolo Grassi, Boon Cher Goh. An open-label, first-in-human study of BAY2927088 in patients with advanced non-small cell lung cancer (NSCLC) harboring an EGFR and/or HER2 mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT126.

Abstract CT202: A first-in-human phase 1 study of LY3537982, a novel, highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C mutant advanced solid tumors (trial in progress)

Abstract Background: KRAS G12C mutations are recurrent oncogenic events in patients (pts) with NSCLC, CRC, and other tumors, and are found in ~14% of NSCLC and 5% of CRC. While KRAS G12C inhibitors have demonstrated activity in pts, overall efficacy may be limited by incomplete target occupancy. LY3537982 is a novel, orally bioavailable, highly selective, and potent inhibitor of the KRAS G12C protein with the potential to deliver >90% target occupancy in pts. In preclinical studies, LY3537982 demonstrated dose-dependent tumor growth inhibition in vivo as a single agent in a KRAS G12C NSCLC PDX model, and robust tumor regression in combination with other agents in vivo in a KRAS G12C sensitive NSCLC model.1 Methods: LOXO-RAS-20001 is an open-label, multi-center, first-in-human Phase 1 study of oral LY3537982 in pts with KRAS G12C-mutant advanced solid tumors. This study consists of 2 parts: Phase 1a dose escalation to evaluate LY3537982 monotherapy and Phase 1b dose expansion to evaluate both LY3537982 monotherapy and in combination. Dose escalation will follow a modified toxicity probability interval-2 (mTPI-2) method, allowing for backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. DLT evaluation period will be 21 days. The primary objective of Phase 1a is to determine the LY3537982 recommended phase 2 dose (RP2D). Part 1b will enroll pts into dose expansion cohorts based on tumor type (NSCLC, CRC, other solid tumors) and prior treatment including KRAS G12C inhibitor refractory NSCLC. Key objectives of Phase 1b are to determine the safety and tolerability of LY3537982 monotherapy, and in combination with various agents: abemaciclib, erlotinib, cetuximab, an investigational ERK inhibitor (LY3214996), an investigational Aurora A kinase inhibitor (LY3295668), and an anti-PD1 antibody. Key secondary objectives include determining the pharmacokinetic properties, and antitumor activity of LY3537982 based on overall response rate (ORR), progression-free survival (PFS), time to response (TTR), and duration of response (DOR) per RECIST v1.1. Eligible pts must have measurable disease per RECIST v1.1, have a KRAS G12C mutation in tumor tissue or ctDNA, have locally advanced, unresectable and/or metastatic cancer per disease specific criteria, and be appropriate candidates for experimental therapy or refused available therapy. Additionally, pts must be ≥18 years old, have ECOG PS of 0-1, and have adequate organ function. Key exclusion criteria include presence of serious cardiac conditions, interstitial lung disease, symptomatic CNS malignancy, symptomatic CNS metastasis, or carcinomatous meningitis. The trial is currently enrolling patients (NCT04956640).

Impact of Somatic Mutations on the Outcome of Children and Adolescents with Therapy-Related Myelodysplastic Syndrome

Myelodysplastic syndromes (MDS) following chemo- and/or radiotherapy for primary malignancy in childhood are clinically heterogeneous and generally resistant to therapy. Current knowledge about the clinical course and the underlying genetic background is imprecise with the exception of structural complex karyotype indicating a particular dismal prognosis. Here, we employed a next generation sequencing (NGS) of 28 genes previously established to assess the mutational landscape in primary pediatric MDS. Using Ampliseq PCR enrichment and Miseq NGS we deep sequenced DNA from bone marrow of 80 patients (pts) with therapy-related MDS (t-MDS) included in the registry of the European Working Group of MDS in Childhood (EWOG-MDS). The 41 males and 39 females had been diagnosed of t-MDS at a median age of 13 years (yrs, range 1.2-22) following treatment of hematopoietic malignancy (HM, 44), solid tumor (ST, 22) or brain tumor (BT, 14). The interval from primary malignancy to t-MDS was 3.2 yrs (0.5-18.5). Morphology was compatible with refractory anemia with excess of blast (RAEB, 34), RAEB in transformation (RAEB-t, 9), MDS related acute myeloid leukemia (MDR-AML, 4), chronic myelomonocytic leukemia (CMML, 14) or MDS without increase of blasts (19). Cytogenetic aberrations were seen in 80% of the patients, most frequently monosomy 7 (29%) and a structural complex karyotype (22%) detected in all morphological entities and subgroups of primary malignancy.Mutations were noted in 50% of pts with 1, 2, 3 or 4 genes affected in 33%, 10%, 6% and 1% respectively. Recurrent mutations were identified in RUNX1 (13.8%), TP53 (12.5%), CBL (8.8%), ASXL1 (7.5%), PTPN11 (7.5%), SETBP1 (5.0%), NRAS (5.0%), KRAS (3.8%), BCORL (2.5%), CSF3R (2.5%), HOXA9 (1.3%), EZH2 (1.3%), PTEN (1.3%), JAK3 (1.3%), STAG2 (1.3%), RAD21(1.3%). No mutations were detected in GATA2, CEBPA, GATA1, BCOR, FLT3, JAK2, cKIT, MPL, CTCF, VPS45, CALR, SH2B3. TP53 mutations arose as an isolated genetic event in the majority of cases (8/10) unlike RUNX1 mutations frequently occurring in combination with other genetic lesions (9/11). According to primary malignancy TP53 mutations were detected in all subgroups (14% HM, 63% ST, 14% BT), whereas RUNX1 mutations were absent in the group with prior solid tumor. Mutations in TP53 were strongly correlated with a structural complex karyotype (9/10). With the exception of MDS without increase of blasts characterized by the absence of RAS pathway alterations, the mutational landscape did not segregate with the morphological subtype. With a median follow-up of 5.3 yrs (0.1-13.7) for pts alive and 68/80 pts treated with hematopoietic stem cell transplantation (HSCT), the probability of overall survival (OS) at 5 yrs was 0.44. OS was worse for patients with more advanced disease (RAEB-t/MDR-AML 0.12 vs CMML 0.29 vs RAEB 0.49 vs MDS without increase of blasts 0.61, p=0.07) and t-MDS following solid tumor (ST 0.30 vs HM 0.49 vs BT 0.46, p=0.09). As expected the detection of a structural complex identified a group with a dismal outcome (OS 0.09 vs 0.37 with normal karyotype vs 0.55 with monosomy 7/ 7q- vs 0.62 with other cytogenetic aberrations, p<0.01). Assessing the impact of mutations on outcome, pts with any mutation had a worse outcome compared to pts with no mutation (OS 0.25 vs 0.60, p<0.01). Mutations in TP53 and RAS pathway were associated with a lower OS of 0.00 and 0.19, respectively, whereas RUNX1 mutated cases without TP53 or RAS pathway alteration had an excellent outcome with 5/5 pts being alive.This study demonstrates that the outcome of patients with t-MDS is variable and may currently be best defined by the genes mutated. Although the germline status was not tested in all cases with TP53 mutation, the study indicates that presence of somatic TP53 or RAS pathway mutations will help identifying patients that are at high risk of treatment failure and therefore candidates for experimental therapy. At the same token, the majority of t-MDS patients without these high risk mutations can successfully be treated with HSCT. Thus, future counseling of patients with t-MDS and their parents will require individual molecular genotyping. DisclosuresNo relevant conflicts of interest to declare.

Clinical Relevance of Partial Response in the Marrow (PRm) after Failure of Frontline Induction Chemotherapy for Adults with Acute Myeloid Leukemia (AML)

Introduction: The management of patients with treatment resistant AML (failure to achieve complete remission, CR; or CR with incomplete blood count recovery; CRi) after intensive chemotherapy is an important clinical consideration. Anticipating the benefit of intensive salvage therapy facilitates patient management decisions and counseling. The UK Medical Research Council (MRC) has associated morphologic partial remission (PRm; defined as 5-15% bone marrow blasts) after course 1 of standard-dose cytarabine (SDAC) based induction, with 5yr overall survival (OS) outcomes comparable to achieving CR (42 vs 51%). In contrast, failure to achieve PRm was linked to 5-year OS of 20% (Wheatley, et al 1999). In an MD Anderson study, patients failing initial high-dose cytarabine (HiDAC) based induction had a 6-month OS expectation of only 7% (Ravandi, et al 2010). Less than 1% of patients in this study achieved PR using International Working Group (IWG) criteria (treatment related decrease in marrow blasts to 5-25% with a >50% reduction from baseline and blood count recovery. We therefore sought to verify the prognostic relevance of PRm in patients with treatment resistant AML (no CR/CRi). Patients and treatment: A retrospective cohort of 104 patients failing intensive chemotherapy at 3 Australian hospitals (Alfred Hospital, Melbourne, Princess Alexandra and Royal Brisbane and Women9s Hospitals, Brisbane) was identified. Prior therapy was standard-dose ara-C (SDAC) 100mg/m2 d1-7 in 73% or high-dose ara-C (HiDAC)(³1g/m2 cytarabine per dose for 5-8 doses) in 28% combined with idarubicin 9-12mg/m2 D1-3 as part of induction. For salvage after SDAC failure, the commonest regimens were HiDAC based, fludarabine and cytarabine (FLAG) variants or a second cycle of 7 + 3, the HiDAC group received further HiDAC based therapy, or FLAG based regimens. Outcomes were compared to a contemporaneously treated AML population (n=128) achieving CR/CRi. Results: OS was stratified according to the level of residual bone marrow blasts after induction. Patients with 5-15% residual blasts (PRm) had a median OS of 20.6 mo, compared to only 5.0 mo for patients with a residual blast count >15% (p 0.0001). The proportion of patients with treatment resistant AML (no CR/CRi) achieving PRm was 41%. CR/CRi rates from salvage chemotherapy were 64% for those failing SDAC and 52% for those failing prior HiDAC-based induction (p=0.37). The likelihood of attaining subsequent remission SDAC-based induction failure was not related to PRm status after cycle 1 of therapy (CR/CRi 73%, compared to 66% without prior mPR; p=0.85). In contrast, the response to subsequent salvage chemotherapy was more common after attainment of prior PRm in cycle 1 for those receiving HiDAC-based induction (CR/CRi 83%, compared to 14% without prior PRm; p=0.01). For patients receiving prior SDAC-based induction, median OS was not reached for patients with PRm, compared to only 8 mo for those not achieving PRm (p=0.0006) (Fig 1A). For patients receiving prior HiDAC-based induction, median OS was 45.5 mo for patients with PRm, compared to only 3.3 mo for those not achieving PRm (p Conclusion: in patients with AML failing initial chemotherapy, good long-term outcomes are still achievable, especially if a PRm was achieved after the first course of induction chemotherapy, regardless of whether SDAC or HiDAC induction was delivered. In contrast, patients refractory (no CR or PRm) to induction chemotherapy have a very poor prognosis and should be considered candidates for experimental therapies or allogeneic stem cell transplantation. Assessment for PRm may be a useful prognostic factor when clinical decisions regarding adults with AML failing to achieve CR/CRi after induction therapy are being considered. Disclosures Mollee:Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity9s Board of Directors or advisory committees. Wei:Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity9s Board of Directors or advisory committees; Servier: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity9s Board of Directors or advisory committees; Astra Zeneca: Membership on an entity9s Board of Directors or advisory committees; Bayer: Membership on an entity9s Board of Directors or advisory committees; Roche: Membership on an entity9s Board of Directors or advisory committees.

The genomic landscape of juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 and CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and therefore be candidates for experimental therapies. In addition, there have been few other molecular pathways identified aside from the Ras/MAPK pathway to serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia in order to expand our knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, gene splicing, the polycomb repressive complex 2 (PRC2) and transcription. Importantly, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.

Predictive Value of Minimal Residual Disease (MRD) Monitoring by RQ-PCR in WT1 Positive Patients Entered in the UK MRC AML-15 Trial

Relapse remains the main cause of treatment failure in Acute Myeloid Leukaemia (AML). Some 65% of AML patients lack a specific fusion transcript which can serve as a molecular target for detecting residual disease. However, in over 75% of AML cases, the Wilm's Tumor (WT1) gene is over-expressed and can therefore be used for MRD monitoring by RQ-PCR. The clinical value of serial MRD monitoring in WT1 positive patients was prospectively assessed in the AML-15 Trial which opened in 2002. The trial compared 3 induction regimens (DA v/s ADE v/s FLAG Ida), followed by randomisation in consolidation (courses 3 and 4) to either MACE + MidAC or 2 doses of Ara-C (3g/m2 or 1.5g/m2) and to stop or have a 5th course (Ara-C 1.5g/m2). Patients were also randomised to receive Gemtuzumab Ozogamicin (3mg/m2) at induction and/or consolidation. Adults in the standard and poor risk groups were scheduled to receive an allograft if a matched donor was available. An “in house” WT1 assay used primers/probes covering exons 7 and 8 in the 3′ region of the WT1 gene. WT1 transcripts from BM and PB were measured by real-time quantitative PCR (RQ-PCR) on the 7900 HT ABI machine, at diagnosis, after each course of chemotherapy, stem cell transplant, and during remission for up to 3 years. WT1 copies were normalised to ABL gene and expressed per 105ABL copies. WT1 was over-expressed in >80% of AML cases screened, when compared to normal BM copies (median 544, range 31–1173), PB (median 10, r 0–58), PBSC (median 71, r 0–483). In this study, 700 patients (excluding Core Binding Factor positive AML) with diagnostic BM WT1 levels >104 copies have been recruited and data on 416 are presented. Follow up is complete to 1/1/08 with 244 relapses after a median follow-up of 40 months. At complete remission (CR) following induction, a greater log reduction in WT1 transcripts was associated with a significantly reduced relapse risk even after adjustment for age, WBC, cytogenetics, performance status and de Novo/Secondary AML (hazard ratio (HR) 0.57 (0.46–0.71) per log reduction p<0.0001). The 5yr relapse rates (RR) for patients with a log reduction of <2, 2–3, and 3 or more were 77%, 50% and 26% respectively (p <0.00001). Furthermore, presence or absence of a 2 log reduction adds to the MRC risk index (developed to identify patients who might benefit from transplant or be candidates for experimental therapies, Burnett et al. ASH 2006, Abstract 18) for survival from CR (HR 0.59 (0.37–0.91), p=0.02). With respect to post induction WT1 transcripts, there were naturally three groups for both BM and PB levels for relapse risk: <1000, 1000–4999, 5000+ copies for BM (5 yr RR 45%, 74%, 82%, p<0.0001 ) and <1000, 1000–2999 and 3000+ copies for PB (5yr RR 53%, 82%, 91%, p<0.0001). After consolidation/SCT, BM and PB transcript levels were also highly predictive of relapse: BM <5000 copies RR 37%, BM 5000+ copies RR 84% (p<0.0001); PB <1000 copies RR 32%, PB 1000+ copies RR 90% (p<0.0001). Looking at all data together, in a multivariate analysis adjusted for MRC risk group, the most important prognostic variables for relapse, relapse free survival and overall survival were post induction log reduction and post chemotherapy PB transcript level >500 copies. In all cases PB transcript levels were more prognostic than levels from BM. We conclude that MRD monitoring in WT1 positive AML patients allows risk stratification based on treatment response, and in this group of patients, MRD monitoring adds to already known risk factors. Whether patients identified as being at high risk of relapse benefit from further treatment, including allogeneic stem cell transplantation, remains to be determined in future studies.

Fludarabine/intermediate-dose cytarabine with or without allogeneic hematopoietic stem cell transplantation in poor-risk leukemia: a single center experience

Disease recurrence has been and remains the leading cause of treatment failure in patients with high-risk leukemia. We retrospectively analyzed outcome in 61 patients with high-risk leukemia receiving a combination of fludarabine and intermediate-dose cytarabine as induction (n = 11) or salvage therapy (n = 35). Thirty-six patients having a suitable stem cell donor proceeded to allogeneic hematopoietic stem cell transplantation (HSCT). Ten patients received fludarabine-based salvage therapy without consecutive allogeneic transplantation and 15 patients received fludarabine/intermediate-dose cytarabine because of disease relapse following allogeneic stem cell transplantation. In patients without prior allogeneic HSCT (n = 46) the complete remission rate (CR) was 41% with a CR rate of 46 and 14% in patients with acute myeloid leukemia (AML) and with acute lymphoblastic leukemia (ALL), respectively. Overall survival for patients achieving a CR was 41 versus 0% for patients not achieving CR (P < 0.0001). The best outcome was observed in patients receiving an allogeneic HSCT in CR following fludarabine/ intermediate-dose cytarabine (47 vs. 0% for patients not in CR at the time of allografting, P = 0.01). All 10 patients receiving fludarabine/intermediate-dose cytarabine without subsequent allogeneic HSCT died within 3 years either of disease relapse/progression or infection. Only 1/15 (7%) patients receiving fludarabine/intermediate-dose cytarabine because of relapse following allogeneic HSCT became a long-term survivor. By multivariate analysis achieving CR, receiving an allogeneic HSCT, and being in first relapse or untreated were the only parameters that significantly determine the outcome. Although preliminary only high-risk AML patients having a stem cell donor are candidates for fludarabine/intermediate-dose cytarabine and only those achieving a CR should be referred to subsequent allogeneic HSCT. All other patients with high-risk leukemia are candidates for experimental therapies within controlled trials.

A Sensitive Risk Score for Directing Treatment in Younger Patients with AML.

Treatment strategies for younger patients (<60 years) with AML who enter complete remission (CR) are frequently decided on a risk assessment based on cytogenetic characterisation. Most collaborative groups have devised prognostic cytogenetic groupings of favourable, intermediate or poor risk which have relapse risks of 25–35%, 50–60%, and 80–85% respectively. The precise lesions in each group might vary by study group, but the overall discrimination is consistent. Favourable and possibly intermediate risk cases may not receive transplantation, whereas poor risk cases will. Outcomes for poor risk cases have failed to improve over the years, and if not transplanted these patients are candidates for experimental therapy. There is concern that cytogenetic segregation may not on its own be sufficiently sensitive on an individual patient level, and the inclusion of other factors may better customise risk. We performed a Cox regression analysis on 1937 non-APL cases with complete data who entered CR in the MRC AML10 and 12 trials. Increasing age, cytogenetic risk group higher WBC, male sex, secondary disease, and incomplete response to course 1 were all identified as significantly (p= 0.05) associated with poorer survival. These respectively contributed 0.013 per year, 0.651 per cytogenetic group, 0.002 per WBC unit (/nl), 0.170 for males, 0.221 for secondary disease, and 0.195 for PR/ 0.390 for resistant disease following course 1 to an individual's total risk score. The groups were separated into scores of <2.00 (good risk), 2.00–2.667 (standard) and >2.667 (poor risk) which gave excellent discrimination for survival from CR at 5 years of 63%, 47% and 24% (p<0.00001). The score was prospectively validated in 897 patients who entered the MRC AML15 trial and was confirmed to be predictive with survivals from CR of 69%, 61% and 42% (p<0.00001). The value of the new score was to move patients out of the old cytogenetic category. The major effect was to move 274 patients from intermediate risk to poor risk and 42 poor risk patients to intermediate risk (table). This score has implications for treatment approach since, relatively, 60% more patients were identified as high risk and are therefore candidates for experimental therapy, or may, from Mantel-Byar analysis, benefit from transplantation.MRC Risk GroupTotalGoodStandardPoorNew Risk ClassificationGood309280337 (14%)Standard511288421381 (59%)Poor2274353629 (27%)Total362 (15%)1590 (68%)395 (17%)2347Crosstabulation of old and new risk group classification

Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999

AbstractCerebral X-linked adrenoleukodystrophy (X-ALD) is a disorder of very-long-chain fatty acid metabolism, adrenal insufficiency, and cerebral demyelination. Death occurs within 2 to 5 years of clinical onset without hematopoietic cell transplantation (HCT). One hundred twenty-six boys with X-ALD received HCT from 1982 to 1999. Survival, engraftment, and acute graft-versus-host disease were studied. Degree of disability associated with neurologic and neuropsychological function and cerebral demyelination were evaluated before and after HCT. Complete data were available and analyzed for 94 boys with cerebral X-ALD. The estimated 5- and 8-year survival was 56%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Demyelination involved parietal-occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. Overall 5-year survival of 92% in patients with 0 or 1 neurologic deficits and magnetic resonance imaging (MRI) severity score less than 9 before HCT was superior to survival for all others (45%; P < .01). Baseline neurologic and neuropsychological function, degree of disability, and neuroradiologic status predicted outcomes following HCT. In this first comprehensive report of the international HCT experience for X-ALD, we conclude that boys with early-stage disease benefit from HCT, whereas boys with advanced disease may be candidates for experimental therapies.

Management of systemic sclerosis: the art and science.

There have been substantial strides in the therapy of systemic sclerosis (SSc) in recent years, particularly in the management of individual organ manifestations. Effective treatments are available for SSc renal crisis and many of the gastrointestinal manifestations of the disease. Raynaud's phenomenon, a nearly universal problem in SSc, also may be effectively managed. Treatment of the pulmonary complications, pulmonary hypertension and interstitial lung disease, remains difficult. Patients with early, diffuse SSc are the best candidates for experimental therapies intended to modify the overall disease process. Most disease-modifying agents have been directed at the fibrotic and inflammatory processes characteristic of SSc and have achieved little success. Future therapies may target mediators of vascular dysfunction in SSc. The success of future therapeutic trials will depend on collaborative efforts between treatment centers.

Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system.

We treated 18 clinically definite relapsing-remitting MS patients with recombinant gamma interferon in a pilot study designed to evaluate toxicity and dosage. Patients received low (1 microgram), intermediate (30 micrograms), or high (1,000 micrograms) doses of interferon by intravenous infusion twice a week for 4 weeks. Serum levels of gamma interferon were proportional to dose and no interferon was detected in CSF. Seven of the 18 patients had exacerbations during treatment, a significant increase compared with the prestudy exacerbation rate (p less than 0.01). Exacerbations occurred in all three dosage groups and were not precipitated by fever or other dose-dependent side effects. There were significant increases in circulating monocytes bearing class II (HLA-DR) surface antigen, in the proliferative responses of peripheral blood leukocytes, and in natural killer cell activity. These results show that systemic administration of gamma interferon has pronounced effects on cellular immunity in MS and on disease activity within the CNS, suggesting that the attacks induced during treatment were immunologically mediated. Gamma interferon is unsuitable for use as a therapeutic agent in MS. Agents that specifically inhibit gamma interferon production or counteract its effects on immune cells should be investigated as candidates for experimental therapy.