Leslie Lehmann

Childhood T-Cell Acute Lymphoblastic Leukemia: The Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Experience

PURPOSE T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL). Historically, T-ALL patients have had a worse prognosis than other ALL patients. PATIENTS AND METHODS We reviewed the outcomes of 125 patients with T-ALL treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium trials between 1981 and 1995. Therapy included four- or five-agent remission induction; consolidation therapy with doxorubicin, vincristine, corticosteroid, mercaptopurine, and weekly high-dose asparaginase; and cranial radiation. T-ALL patients were treated the same as high-risk B-progenitor ALL patients. Fifteen patients with T-cell lymphoblastic lymphoma were also treated with the same high-risk regimen between 1981 and 2000. RESULTS The 5-year event-free survival (EFS) rate for T-ALL patients was 75% +/- 4%. Fourteen of 15 patients with T-cell lymphoblastic lymphoma were long-term survivors. There was no significant difference in EFS comparing patients with T-ALL and B-progenitor ALL (P =.56), although T-ALL patients had significantly higher rates of induction failure (P <.0001), and central nervous system (CNS) relapse (P =.02). The median time to relapse in T-ALL patients was 1.2 years versus 2.5 years in B-progenitor ALL patients (P =.001). There were no pretreatment characteristics associated with worse prognosis in patients with T-ALL. CONCLUSION T-ALL patients fared as well as B-progenitor patients on DFCI ALL Consortium protocols. Patients with T-ALL remain at increased risk for induction failure, early relapse, and isolated CNS relapse. Future studies should focus on the identification of and treatment for T-ALL patients at high risk for treatment failure.

A Modified γ-Retrovirus Vector for X-Linked Severe Combined Immunodeficiency

BACKGROUND In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1. METHODS We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc). RESULTS All patients received bone marrow-derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2, MECOM, and other lymphoid proto-oncogenes in our patients. CONCLUSIONS This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.).

Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma

Children with neuroblastoma receiving high-dose carboplatin as part of their conditioning regimen for autologous marrow transplantation have a high incidence of speech frequency hearing loss. We evaluated hearing loss in 11 children with advanced stage neuroblastoma who underwent autologous marrow transplantation, following a conditioning regimen containing high-dose carboplatin (2 g/m2, total dose). Audiometric evaluations were obtained at diagnosis, prior to and following transplant. Exposure to other known ototoxins also was assessed. All patients sustained worsening of hearing following high-dose carboplatin. Nine of the 11 children (82%) had evidence of speech frequency hearing loss post transplant for which hearing aids were recommended (grades 3–4). Three of the nine children had speech frequency loss prior to transplant which progressed following transplant. The entire group was heavily pre-treated with platinum-containing chemotherapy pre-BMT and had extensive exposure to other ototoxins, including aminoglycoside antibiotics, diuretics, and noise exposure – all of which could have exacerbated the effects of carboplatin. High-dose carboplatin is ototoxic, particularly in patients who have been primed with previous platinum therapy or other ototoxic agents. We conclude that further efforts are needed to monitor and minimize this complication. In cases where hearing loss is inevitable due to cumulative ototoxic exposures, families need to be adequately prepared for the tradeoffs of potentially curable therapy.

Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure.

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.

End-of-life experience of children undergoing stem cell transplantation for malignancy: parent and provider perspectives and patterns of care

The end-of-life (EOL) experience of children who undergo stem cell transplantation (SCT) may differ from that of other children with cancer. To evaluate perspectives and patterns of EOL care after SCT, we surveyed 141 parents of children who died of cancer (response rate, 64%) and their physicians. Chart review provided additional information. Children for whom SCT was the last cancer therapy (n = 31) were compared with those for whom it was not (n = 110). SCT parents and physicians recognized no realistic chance for cure later than non-SCT peers (both P < .001) and were more likely to have a primary goal of cure at death (parents, P < .001; physicians, P = .02). SCT children were more likely to suffer highly from their last cancer therapy and die in the intensive care unit (both P < .001), with less opportunity for EOL preparation. SCT parents who recognized no realistic chance for cure more than 7 days before death along with the physician were more likely to prepare for EOL, and if their primary goal was to reduce suffering, to achieve this (P < .001). SCT is associated with significant suffering and less opportunity to prepare for EOL. Children and families undergoing SCT may benefit from ongoing discussions regarding prognosis, goals, and opportunities to maximize quality of life.

A Murine Xenograft Model for Human CD30+ Anaplastic Large Cell Lymphoma: Successful Growth Inhibition with an Anti-CD30 Antibody (HeFi-1)

To develop a model for the biology and treatment of CD30+ anaplastic large cell lymphoma (ALCL), we transplanted leukemic tumor cells from a 22-month-old girl with multiple relapsed ALCL. Tumor cells were inoculated intraperitoneally into a 4-week-old SCID/bg mouse and produced a disseminated tumor within 8 weeks; this tumor was serially transplanted by subcutaneous injections to other mice. Morphology, immunohistochemistry, and molecular genetics which demonstrated the NPM-ALK fusion protein, resulting from the t(2;5)(p23;q35), confirmed the identity of the xenograft with the original tumor. The tumor produced transcripts for interleukin-1alpha, tumor necrosis factor-alpha, and interferon-gamma which could explain the patients B-symptoms. Treatment of mice with monoclonal antibody (HeFi-1) which activates CD30 antigen administered on day 1 after tumor transplantation prevented tumor growth. Treatment with HeFi-1 after tumors had reached a 0.2 cm(3) volume caused tumor growth arrest and prevention of tumor dissemination. We conclude that transplantation of CD30+ ALCL to SCID/bg mice may provide a valuable model for the study of the biology and design of treatment modalities for CD30+ ALCL.

Hematopoietic cell transplantation comorbidity index predicts transplantation outcomes in pediatric patients

Quantifying the risk of hematopoietic cell transplantation (HCT)-related mortality for pediatric patients is challenging. The HCT-specific comorbidity index (HCT-CI) has been confirmed as a useful tool in adults, but has not yet been validated in children. We conducted a retrospective cohort study of 252 pediatric patients undergoing their first allogeneic HCT between January 2008 and May 2009. Pretransplantation comorbidities were scored prospectively using the HCT-CI. Median age at transplantation was 6 years (range, 0.1-20) and median follow-up was 343 days (range, 110-624). HCT-CI scores were distributed as follows: 0, n=139; 1-2, n=52; and 3+, n=61. The 1-year cumulative incidence of nonrelapse mortality (NRM) increased (10%, 14%, and 28%, respectively; P<.01) and overall survival (OS) decreased (88%, 67%, and 62%, respectively; P<.01) with increasing HCT-CI score. Multivariate analysis showed that compared with score 0, those with scores of 1-2 and 3+ had relative risks of NRM of 1.5 (95% confidence interval, 0.5-4.3, P=.48) and 4.5 (95% confidence interval, 1.7-12.1, P<.01), respectively. These results indicate that the HCT-CI score predicts NRM and OS in pediatric patients undergoing HCT and is a useful tool to assess risk, guide counseling in the pretransplantation setting, and devise innovative therapies for the highest risk groups.

Bronchiolitis obliterans following pediatric allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans (BrOb) is a well-recognized complication of allogeneic hematopoietic stem cell transplantation (HSCT). It is associated with substantial morbidity and mortality in adult patients. However, the incidence and morbidity of this complication have not been well described in the pediatric population. We report our experience of BrOb in 216 pediatric allogeneic HSCT patients between 1 January 2001 and 31 December 2005. In total 18 of 216 patients developed BrOb during this time. The diagnosis of BrOb was based on pulmonary function abnormalities, radiographic findings or lung biopsy. In total 14 of 18 patients with BrOb received stem cells from unrelated donors. In total 17 of 18 patients received bone marrow as a stem cell source, and 1 received peripheral blood stem cells. All pediatric patients in this report had a known risk factor for BrOb, most commonly chronic GVHD (l8 of 18 patients). Additionally, 7 of 18 patients had either toxic lung injury or virally mediated pulmonary disease before the diagnosis of BrOb. With a median of 45.1 months of follow-up, the outcomes were 5 of 18 patients died of lung disease, 2 died of other causes, 3 had progressive lung disease, 6 achieved partial resolution of disease and 2 had stable disease. BrOb, while uncommon, is associated with considerable morbidity and mortality in pediatric HSCT.

How we treat oral chronic graft-versus-host disease

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation that is associated with a diminished quality of life. The oral cavity is frequently affected, with a wide variety of signs and symptoms that can result in significant short- and long-term complications ranging from mucosal sensitivity and limited oral intake to secondary malignancy and early death. This article provides a comprehensive approach to the diagnosis and clinical management of patients with oral cGVHD, with particular attention to differential diagnosis, control of symptoms, and prevention of and screening for secondary complications. The clinical considerations and recommendations presented are intended to be practical and relevant for all clinicians involved in the care of patients with oral cGVHD, with the ultimate goal of improving care and outcomes.

Late effects in children treated with intensive multimodal therapy for high-risk neuroblastoma: High incidence of endocrine and growth problems

Due to the poor prognosis of high-risk (HR) neuroblastoma (NBL), scant data exist on late effects after treatment. Recently, protocols utilizing intense multimodal treatment have resulted in improved long-term survival. The objective of this study was to determine the prevalence of late effects in survivors of HR NBL. A retrospective review of clinical data for serial patients completing treatment between September 1994 and October 2007 and surviving for at least 1 year was performed. Therapy included aggressive chemotherapy, surgery, radiation and single or tandem SCT. Oncology follow-up was standard; clinical criteria were utilized for referrals to endocrinology and other services. Fifty-one eligible patients were identified. Median follow-up was 6.1 years (range 1.0–15.2). Height was significantly impacted (ΔZ-score −1.91 in those treated with TBI and −0.77 in those without). Pre-diabetes or diabetes, hypothyroidism and ovarian insufficiency were observed in 50, 59 and 75% of at-risk survivors, respectively. Hearing loss and dental issues were common. Nine patients had relapse of NBL; seven died of progressive disease. As there is a high prevalence of late effects in long-term survivors of HR NBL, close monitoring and further studies after treatment are indicated, and in particular after more modern, non-TBI regimens.