Early Bone Marrow Transplantation Research Articles

The effects of early and late bone marrow transplantation in siblings with alpha‐mannosidosis. Is early haematopoietic cell transplantation the preferred treatment option?

This article documents both the neurological and physical outcomes of the first published set of siblings undergoing transplantation at differing ages for α-mannosidosis. The older brother, the index case, was diagnosed at the age of 3years and underwent transplantation at 13years for the treatment of increasing somatic problems and recurrent infections. The younger brother had undergone transplantation pre-symptomatically at 6months of age. Their clinical, radiological and developmental outcomes are documented and compared with the previous published cases, with the case for early transplantation being weighted against other potential therapies.

Telomerase Gene Mutation Screening and Telomere Length Detection in Chinese Patients with Bone Marrow Failure Syndrome.

Background Acquired bone marrow failure syndrome (BMF) is a group of diseases include aplastic anemia(AA), melodysplastic syndrome (MDS) and paraoxymal nocturnal hemoglobinuria (PNH). Some BMF patients have short telomeres in their peripheral nucleated cells. The length of telomere is maintained by a group of enzymes called telomerase complex. The core components of this complex are a RNA template and a reverse transcriptase, called TERC and TERT, respectively. Recently several studies in the west and Japan have disclosed the presence of telomerase complex gene mutation in a small group of patients with acquired bone marrow failure. They speculated that this small group of patients might represent a subset of cryptogenic Dyskeratosis Congenita (DKC), in which the premature exhaustion of hematopoietic reservoir is caused by mutations in the telomerase gene. This group of patients, though very small in number, would benefit from early bone marrow transplantation instead of traditional immunosuppressive therapy. The incidence of aplastic anemia in Chinese people is relatively high compared with that in the western country. But there has so far been no study in China about the incidence of telomerase gene mutation in acquired bone marrow failure and its relationship with telomere length.Objectives To study the incidence of telomerase gene (namely TERC and TERT ) mutation in Chinese patients with acquired bone marrow failure and explore its relationship with telomere shortening.Methods Blood samples from 90 patients with AA, MDS, and PNH in northern China were collected and performed TERC and TERT mutation analysis. Telomere length was measured by Southern blotting and compared with their normal counterparts.Results 2 TERC mutations (n37 A→G, reported previously ; n66G→C) and 2 TERT mutations (n1870G→T (E/*); n1780G→T (S/I) ) were identified in 90 BMF patients. Among them, 3 mutations are reported first time. 1 patient with TERT mutation, however, was finally diagnosed as DKC instead of acquired AA, making the incidence of telomerase gene mutation in Chinese people with acquired bone marrow failure 3.4%, similar to that of the western people. Southern Blot analysis showed the small group of patients carrying TERC and TERT mutations has very short telomeres, compared with normal controls and with their aplastic counterparts.Conclusions The incidence of telomerase gene mutation in Chinese people with acquired bone marrow failure is 3.4%, similar to that of the western people. This small group of patients has very short telomeres, it is thus clinically important to screen for this small group of patients.

Uncovering a Pediatric Immunodeficiency Part 2

In Part I of this series the diagnosis of a pediatric immunodeficiency was discussed. In that article key history and exam findings were discussed to help alert the clinician to a problem. Part II will further the knowledge of immunodeficiencies by describing some of the common immunodeficiencies. Diseases affecting neutrophil granule function, specific B-cell or T-cell function, combined T and B cell function and newer syndromes that have multi-system involvement, their diagnosis, and treatment are presented here. The genetic links for many of these diseases are known, and described in this article. Today most large medical centers are able to perform the appropriate diagnostic testing to assure early diagnosis and rapid treatment with aggressive antibiotic regimens and intravenous immunoglobulin. In many cases early bone marrow transplantation is curative or vital to survival. The diagnosis of an immunodeficiency in a child can be overwhelming to the family as well as the primary care clinician. A well armed clinician, knowledgable in the principles of immunodeficiencies, their diagnosis, and treatment can be an active and vital member of the multi-disciplinary team that will care for these challenging children.

Aberrant DNA Methylation of a Cell Cycle Regulatory Pathway Composed of p73, p15 and P57kip2 Is Associated with Poor Prognosis in Adult Patients with Philadelphia Chromosome Negative Acute Lymphocytic Leukemia (ALL).

Aberrant DNA methylation of promoter-associated CpG islands is a frequent event in ALL. The high frequency of aberrant DNA methylation observed in patients with ALL, and the fact that these epigenetic changes are also present at relapse suggest that aberrant DNA methylation has a role in the pathogenesis of the disease. The identification of subgroups of patients with poor prognosis based on their methylation characteristics may translate in specific clinical interventions, such as the introduction of early allogeneic bone marrow transplantation or the use of hypomethylating agents. In initial studies, we have shown that methylation of more than 1 gene of a cell cycle regulatory pathway composed of p73, p15 and p57KIP2 occurs in close to 25% of patients, and is associated with a poor prognosis in patients with Philadelphia chromosome negative (Ph negative) disease (Blood 2003; 101:4131). Of importance, protein expression of this pathway was associated with a significant better prognosis by multivariate analysis (JCO 2005; 23:3932–9). To confirm the prognostic value of methylation of p73, p15 and p57KIP2, we are conducting an NCI-sponsored large-scale study of 300 patients wit Ph negative ALL at the time of initial presentation. As part of this study, and based on the original statistical design, we have performed an interim analysis of the first 93 patients studied. The objective of this interim analysis was to terminate this study early in case of a high likelihood that the study will be negative: that is that methylation of triad of genes is not associated with a poor prognosis. To detect DNA methylation, we have developed a new real-time bisulfite PCR assay. This method allows for the simultaneous analysis of multiple samples in less than 24 hours, is quantitative, and requires less than 0.2 ug of DNA for each gene. To amplify bisulfite treated DNA, we designed primer sets and probes for all three genes in regions known to be inversely correlated with gene expression. To quantify methylation density, we used the interferon gamma (INFG) gene as an internal control because it has very rare CpG sites, is a single copy gene and has no homology with other known genes. The characteristics of the patients are similar to those of the initially reported cohort of patients (Blood 2003; 101:4131–6). The median overall survival (OS) of the whole group was 166 weeks. Out of the 93 patients, 88 (94%) achieved a complete remission. And out of these 88 patients, 37 (42%) eventually relapsed. The median disease-free survival was 127 weeks. P57KIP2 was methylated in 24% of patients, p15 in 34% and p73 in 21%. Methylation of more than 1 gene of this triad was observed in 19% of patients. This subgroup of patients had a median OS of 50 weeks. By multivariate analysis, methylation of more than 1 gene of this pathway (hazard ratio 4.07, 95% CI 1.63–7.5, p=0.003), presence of the CALLA antigen, older age, increased WBC and lower platelet count were associated with a significantly worse prognosis. Based on this interim analysis, this study continues, and will be completed by the time of the meeting. These results indicate that analysis of methylation markers may have a role in the prognostication of patients with Ph negative ALL.

Early Allogeneic Bone Marrow Transplantation for Young Adults with Acute Myeloid Leukemia in First Complete Remission: The 17 Year Experience of the BGMT Group.

Background. From 1984 and during 17 years, the BGMT inter-group prospectively followed the same strategy of early allogeneic bone marrow transplantation (alloBMT) compared to non allogeneic treatment in 4 consecutive trials, as modality of consolidation for patients (pts) under 45 with an HLA identical sibling donor in first complete remission (CR) of an acute myeloid leukemia (AML). The purpose of this study was to evaluate this strategy by an intent to treat analysis based on donor availability.Pts and methods. In each of these trials, pts received an induction by daunorubicine 60 mg/m2/d 3d + cytarabine 100 mg/m2/d (CI) 10 d. followed by a light consolidation based on cytarabine 50 mg/m2/12h SC 7d + daunorubicine 60 mg/m2/d 2d. Pts under 45 with a sibling donor had an alloBMT (cyclophosphamide 60 mg/kg IV 2d + fractionated TBI 12 Gy) without any further chemotherapy. If not, pts were treated according to a strategy of chemotherapy which evolved the years according to experience and knowledge. The 182 pts with a donor were compared to the 290 who had not. The median age of these pts (M/F = 103/79 vs 154/136) was 34 vs 33.5 years (15–45). Median WBC count was 15 vs 16 (0.2–35) and WBC was ? 30 109/L for 65 vs 94 pts. The FAB distribution was: M1/M2 = 92 vs 150; M3 = 10 vs 14; M4/M5 = 63 vs 110; M0/M6/M7 = 17 vs 16. The cytogenetics risk groups distribution was: low risk = 32 vs 62 (24 vs 28%); intermediate risk = 78 vs 127 (58 vs 57%); high risk = 24 vs 34 (18 vs 15%). CR was achieved in 2 courses for 19 vs 42 pts (10 vs 14 %).Results. AlloBMT was done for 90.7% of the eligible pts. With a median follow-up of 114 months, 10-year cumulative incidence of relapse and non relapse death, overall survival and leukemia free survival (LFS) were 27.2% vs 54.5% (p < .001), 24.4% vs 5.6% (p < .001), 51.2% vs 43.4% (p = .11), and 48.3% vs 39.9% (p < .03), respectively. For all patients, univariate and multivariate analysis found that initial WBC count, FAB subtypes, cytogenetic risk group, number of course to achieve CR, demonstrated a significant prognosis influence. A better LFS was observed in the donor group among patients with M1 to M5 FAB subtypes (52.4% vs 41.9% (p < .01)), among those with WBC > 30 109/L (47.3% vs 30.7% (p < .02)), and among those of the intermediate cytogenetic risk group (58% vs 43% (p < .01)). For low cytogenetic risk group no difference was shown between donor an no donor group (58.6% vs 65.9% (p =.63). In this study, alloBMT presents limitations in the most aggressive diseases such as M0/M6/M7 FAB subtypes (11.8% vs 6.3% (p = .15)) or high cytogenetic risk group (12.5% vs 7.8% (p = .67). In this situation it does not seem to be sufficient enough to control disease by the graft versus leukemia effect alone. For these pts new investigations should be undertaken.

Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial

AbstractVarious transplantation strategies have been designed to improve the poor prognosis of adult (ages 15 to 60 years) acute lymphoblastic leukemia (ALL). The GOELAL02 trial evaluated the impact of early allogeneic bone marrow transplantation (alloBMT) or delayed unpurged autologous stem cell transplantation (ASCT) for patients who had no human leukocyte antigen (HLA)–matched sibling donor or who were older than 50 years. Inclusion criteria included at least one of the following: age older than 35 years; non–T-ALL; leukocytosis greater than 30 × 109/L; t(9;22), t(4;11), or t(1; 19); or failure to achieve complete remission (CR) after one induction course. Among 198 patients, the median age was 33 years. The CR rate was 80% with vincristine, idarubicine, l-asparaginase, and randomized intravenous injection or oral steroids (P = nonsignificant [ns]). AlloBMT was performed after 2 consolidation courses while ASCT was delayed after 1 additional reinduction. Intensified conditioning regimen before transplantation included etoposide, cyclophosphamide, and total body irradiation (TBI). Median follow-up was 5.1 years. The median overall survival (OS) was 29 months, with a 6-year OS of 41%. On an intent-to-treat analysis for patients younger than 50 years, alloBMT significantly improved the 6-year OS (75% versus 40% after ASCT; P = .0027). Randomized interferon-α maintenance had no effect on relapse or survival after ASCT. In conclusion, the outcome of adult ALL is better after early alloBMT than after delayed ASCT.

Molecular characterization of three novel Fanconi anemia mutations in Israeli Arabs.

In a previous study, we investigated the molecular basis of Fanconi anemia (FA) in 13 unrelated Israeli Jewish FA patients and identified four ethnicity specific mutations. In the present study we extended our study to Israeli Arab patients. We studied three consanguineous families with nine FA patients and an additional unrelated patient. DNA single-strand conformation polymorphism of each exon of the FANCA and FANCG genes was followed by sequence analysis of the aberrantly migrating fragments and by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of the splice-site mutations identified. Three unique disease-causing mutations were identified: (i) FANCA gross deletion of exons 6-31; (ii) FANCA splice-site mutation IVS 42-2A>C; (iii) FANCG splice-site mutation IVS4+3A>G. Sequence analysis of the FANCA gross deletion revealed recombination between two highly homologous Alu elements. cDNA analysis of the two splice mutations suggested intron 42 retention in FANCA IVS 42-2A>C and exon 4 skipping in FANCG IVS4+3A>G. The clinical condition of eight patients with FANCA mutations was severe. Two unique FANCA mutations and one FANCG mutation were identified in Israeli Arab FA patients. Deletion of FANCA exon 6-31 as in previously described gross deletions was within introns rich in Alu repeats. To the best of our knowledge, the FANCA IVS 42-2A>C mutation is the first in this gene to result in intron retention. Further analysis of FA mutations will enable prenatal diagnosis and a rational therapeutic approach including frequent monitoring and early bone marrow transplantation.

Report of six cases of chediak-higashi syndrome with regard to clinical and laboratory findings.

Chediak - Higashi Syndrome (CHS) is a rare, primary Immunodeficiency disorder with an autosomal recessive (AR) inheritance and characterized by recurrent infection, partial occulocutaneous albinism and an accelerated phase.In this report we describe clinical and laboratory findings from 6 CHS patients. Clinical and laboratory information of six patients who were referred to our center during the last 20 years (from 1983 - 2003) were reviewed.Onset age of disease was between 3 months to 10 years. All patients had history of consanguineous parents and two patients were siblings. All patients had oculocutaneous albinism, nystagmus, recurrent infections which included upper and lower respiratory tract (U and LRT) infections, stomatitis, thrush, and skin abscesses and hepatitis. In laboratory findings, all patients had neutropenia and normal immunoglobulins and normal CD3, CD4, CD8 and CD19 lymphocyte by flowcytometry and three of the four patients had chemotatic defect. Five patients certainly had giant granule in bone marrow neutrophil and in one patient it was equiovocal. Three patients had an accelerated phase, and for one patient bone marrow transplantation was done that was tolerated well and had been well after 7 years.We emphasize the need for early diagnosis on basis of characteristic facies and diagnostic laboratory examinations and early bone marrow transplantation (BMT) in patients.

Extracorporeal photopheresis in the treatment of graft-vs-host disease.

Graft-vs-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplantation. GVHD was first described by Barnes and Mole as a fatal disease manifest by skin changes, diarrhea, and runting in irradiated mice given allogeneic spleen cells. Early human allogeneic bone marrow transplant patients were noted to manifest a similar syndrome of dermatitis, hepatitis, and enteritis occurring within the first 100 days after infusion of allogeneic stem cells. The etiology of GVHD is related to alloreactivity between immunocompetent donor lymphocytes and transplantation alloantigens on host tissues. The incidence of acute GVHD (aGVHD) ranges from 27% to 50% after sibling-matched related donors and from 42% to 72% after unrelated donor bone marrow or peripheral blood stem cell transplants. Despite aggressive immunosuppressive therapies, including high-dose corticosteroids, cyclosporine A, antithymocyte globulin, tacrolimus, and mycophenolate mofetil, the mortality from acute GVHD remains high. Chronic GVHD (cGVHD) is a syndrome of immune dysregulation whose onset has been arbitrarily defined as occurring at least 100 days after allogeneic stem cell infusion. Clinical features of cGVHD are distinguished from aGVHD in that they more closely resemble autoimmune disorders. Histopathologic changes include sclerodermatous skin changes from collagen deposition, pulmonary fibrosis, esophageal dysfunction, dry mouth or mucocutaneous ulcerations, cholestasis, and myositis or fasciitis and are thought to be initiated, in part, by autoantibodies to cell surface and intracellular proteins. The incidence of cGVHD ranges from 30% in siblingmatched donors to over 70% in matched unrelated donor transplants. Factors associated with cGVHD include increased donor and recipient age, prior aGVHD, and the use of alloimmune female donors. Conventional therapeutic approaches for cGVHD, including corticosteroids and immunosuppressive agents, have demonstrated limited efficacy in patients with extensive disease. Oral methoxsalen followed by ultraviolet A therapy (PUVA), while effective in alleviating the symptoms of chronic skin GVHD, has had no impact on visceral involvement. Novel agents demonstrating activity include T-cell directed therapies, such as humanized anti-CD25 antibody (dacluzimab) and pentostatin, as well as anti-TNF-a antibody (infliximab) and thalidomide. While aGVHD is understood as a disease of acute alloreactivity, the etiology of cGVHD is controversial and is believed to be either an extension of aGVHD and/ or a result of dysfunctional immune reconstitution with generation of autoantibodies and tissue autoreactive Tcell clones. Acute GVHD is believed to be a Th1-driven disease wherein inflammatory cytokines, such as IL-2 and IFN-c as well as the monokines IL-1 and TNF-a, contribute to tissue damage. In murine models, donor CD4-enriched cells of Th2 phenotype have been shown to prevent aGVHD without affecting engraftment, suggesting that they play a role in downregulating the Th1 response, and, in other studies, administration of a Th1 inhibitor (TAK-603) markedly reduced the mortality associated with aGVHD. Chronic GVHD has been proposed by others to be a Th2-mediated disease, but recent studies demonstrating upregulation of Th1 cytokines IFN-c and IL-12 in peripheral blood mononuclear cells implicate, in part, a Th1-derived mechanism similar to that seen in acute alloreactivity.

Long-term follow-up and prognosis of chronic granulomatous disease in Yugoslavia: is there a role for early bone marrow transplantation?

We report the long-term follow-up of 12 pediatric-aged patients with chronic granulomatous disease (CGD). The mean age at the onset of infections was 5 months with a median delay in diagnosis of 2.5 years. Bacille Calmette-Guérin lymphadenitis was the most common presenting infection (6) followed by suppurative lymphadenitis (4), liver abscess (1), or Salmonella sepsis (1). Prophylaxis with cotrimoxazole was recommended to all patients. During the mean follow-up of 10 years (range, 4-23 years) pneumonitis was the most prevalent infection (91%) followed by lymphadenitis (83%), aphtous stomatitis (58%), and liver abscesses (25%). Seven (58%) patients developed chronic lung disease due to grossly delayed diagnosis (3) or poor compliance with antimicrobial prophylaxis (4). Five (41%) patients died during the second decade of life of aspergillosis (3) or chronic lung disease (2). Probability of survival into the third decade of life was estimated to be only 19%. We argue that HLA-identical bone marrow transplantation (BMT), if possible, should be attempted at early age because of significant morbidity and mortality in adolescence. BMT also should be considered in patients who suffer severe infections despite antimicrobial prophylaxis or patients with evidence of chronic lung disease. Possibility of elective BMT from unrelated donors remains to be carefully evaluated.

Idiopathic pneumonia syndrome after syngeneic bone marrow transplant in mice.

Idiopathic pneumonia syndrome is characterized by noninfectious diffuse lung injury after myeloablative chemotherapy and bone marrow transplant. Because little is known about its pathogenesis after autologous-based regimens, we have developed a murine model that closely mimics the human lung disease process. Using an autologous regimen similar to that used for patients with metastatic breast cancer, mice developed pulmonary injury as early as 1 day posttransplant. This lung injury was most dramatically characterized by decreased lung compliance that was associated with an intense monocytic cellular infiltrate of activated macrophages. This influx was preceded by an acute elevation in monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha. The conditioning regimen caused substantial oxidative stress as manifest by elevations in lung lipid peroxidation and oxidized glutathione. To test the hypothesis that oxidation is directly responsible for the lung toxicity, we administered the antioxidant, n-acetylcysteine. These mice showed substantially less lung injury, thus providing direct evidence that oxidative stress plays a distinct role in the development of lung injury in the early periautologous bone marrow transplant period. Attenuation of lung oxidative stress and/or inflammation in patients undergoing autologous bone marrow transplant may reduce the subsequent development of idiopathic pneumonia syndrome.

Reviewing Omenn syndrome.

Omenn syndrome is a form of severe combined immunodeficiency associated with high mortality. Early recognition is required in order to initiate life-saving therapy. This review provides information on the clinical symptoms, laboratory parameters and pathology of the disease, supporting early diagnosis in suspected patients. A literature search was performed using Medline, encompassing the period 1965-1999. Sixty-seven cases were identified and with the addition of a recently diagnosed patient at our hospital, 68 children were included. Median age at onset of symptoms was 4 weeks. Key symptoms were erythematous rash (98%), hepatosplenomegaly (88%), lymphadenopathy (80%), often accompanied by recurrent infections (72%) and alopecia (57%). An elevated WBC (55%) was frequently observed, due to eosinophilia and/or lymphocytosis. B-cell counts were significantly decreased whereas T-cell counts were elevated. A high serum IgE was another frequent finding (91%). Therapeutic options include bone marrow transplantation or cord blood stem cell transplantation; however, the mortality still was 46%. Omenn syndrome is a fatal disease if untreated. The mortality may be reduced when diagnosis is established early and treatment is initiated rapidly by using early compatible bone marrow transplantation or cord blood stem cell transplantation.

Clinical significance of skin biopsies in the diagnosis and management of graft-vs-host disease in early postallogeneic bone marrow transplantation.

To determine the value of skin biopsies in the management of suspected graft-vs-host disease (GVHD) within 30 days of allogeneic bone marrow transplantation (BMT). Retrospective study based on review of a BMT database. Leukemia/BMT ward of a tertiary care, university teaching hospital. One hundred and eighty-seven consecutive patients who received allogeneic BMT between January 1, 1994, and June 30, 1997, at Vancouver General Hospital, Vancouver, British Columbia. (1) Skin biopsy frequency for patients with rashes suggestive of acute GVHD; (2) clinical significance of skin biopsy in the management of patients with suspected acute GVHD after BMT; (3) relationship between severity of clinical GVHD and the likelihood to receive GVHD therapy; and (4) relationship between biopsy status or biopsy result and outcome of BMT (acute and chronic GVHD, transplant-related mortality, and overall and event-free survival). During the early post-BMT period (<30 days after BMT), 88 patients had rashes suggestive of acute GVHD; of these, 51 (58%) underwent skin biopsy to confirm the diagnosis. Skin biopsies were performed more often for higher clinical stages of cutaneous GVHD. There was no significant difference between the patients with positive biopsy findings and those with negative findings, either in the clinical severity of acute GVHD or in likelihood to receive treatment for GVHD. Most (85%) of the patients who underwent biopsies and received GVHD therapy had treatment initiated before skin biopsies were performed or before the results were available. The higher the clinical grade of overall acute GVHD, the more likely it was that the patients were treated for GVHD (P<.001). The outcome of BMT was not influenced by the skin biopsy status or biopsy result. The biopsy findings correlated poorly with the clinical severity of skin rash suggestive of acute GVHD soon after BMT. The decision to treat suspected acute GVHD depended not on skin biopsy findings but rather on clinical severity of acute GVHD. In this regard, skin biopsy has a limited role in the management of patients early after allogeneic BMT.

Intensive short term therapy with granulocyte-macrophage-colony stimulating factor support, similar to therapy for acute myeloblastic leukemia, does not improve overall results for adults with acute lymphoblastic leukemia

Despite modern treatment programs, less than 20% of adult cases of acute lymphoblastic leukemia (ALL) are cured. For relapsing and/or refractory patients, use of high dose cytosine arabinoside (ara-C) and anthracyclin achieved a complete remission (CR) rate of up to a 75%. The aim of this study was to evaluate in adult patients with ALL 1) the CR rate of a chemotherapy schedule similar to a schedule for acute myeloblastic leukemia (AML) patients, 2) the antileukemic value and the tolerance of 3 intensive stage treatments, and 3) the impact of recombinant granulocyte-macrophage-colony stimulating factor (rGM-CSF) on chemotherapy-induced neutropenia and infectious complications, as well as the effect of dose intensity.Between November 1990 and April 1992, 67 patients ages 15-55 years with de novo ALL were randomly assigned to receive either rGM-CSF or placebo. The induction treatment consisted of idarubicin, methylprednisolone, and high dose ara-C. After achieving CR, patients up to age 45 years who had an HLA-identical sibling were assigned to undergo allogeneic bone marrow transplantation (BMT). All remaining patients received a first course of early intensification with high dose ara-C, mitoxantrone, etoposide, and methylprednisolone, followed by autologous, unpurged BMT.Of the 64 eligible patients, 50 (78%) achieved CR. Sixteen allogeneic and 18 autologous BMTs were performed. The median survival was 10.2 months. The 4-year survival was 24%. rGM-CSF only improved the incidence of severe mucositis during the induction course (P = 0.003) and probably also improved the median duration of fever (P = 0.07).This schedule, similar to that for the treatment of AML patients, with early BMT included, did not prove to be a satisfactory approach to the treatment of most adult ALL patients, although CR was achieved in 78% of cases. In this study, no major improvement was obtained with rGM-CSF therapy.

Prednisone Response Is the Strongest Predictor of Treatment Outcome in Infant Acute Lymphoblastic Leukemia

To define prognostic factors in infant acute lymphoblastic leukemia (ALL), the outcome of 106 infants (age </=12 months) during 3 consecutive multicenter trials of the Berlin-Frankfurt-Münster group (ALL-BFM 83, 86, and 90) was retrospectively analyzed according to presenting features and early in vivo response to prednisone. The prednisone response was defined as the cytoreduction (number of blood blasts per microliter at day 8) to a 7-day prednisone prephase and 1 intrathecal dose of methotrexate on day 1. Prednisone good responder (PGR; <1,000 blasts/microL) received conventional therapy and prednisone poor responder (PPR; >/=1,000 blasts/microL) received intensified therapy. Infant ALL was characterized by a high incidence of a white blood cell count greater than 100 x 10(3)/microL (57%), central nervous system leukemia (24%), lack of CD10 expression (59%), 11q23 rearrangement (49%) including the translocation t(4;11) (29%), and a comparatively high proportion of PPR (26%), which were all significantly associated with inferior outcome by univariate analysis. The estimated probability for an event-free survival at 6 years (pEFS) was by far better for PGR compared with PPR, who had a dismal prognosis despite intensified treatment (pEFS, 53% +/- 6% v 15% +/- 7%, P =.0001). Infant PGR, who were less than 6 months of age (n = 40), lacked CD10 expression (n = 43), and/or had an 11q23 rearrangement (n = 17) fared significantly better compared with corresponding PPR, as indicated by a pEFS of 44% +/- 8%, 49% +/- 8%, and 41% +/- 12%, respectively. In multivariate analysis, PPR was the strongest adverse prognostic factor (relative risk, 3.3; 95% confidence interval, 1.9 to 5.8; P <.0001). Infants with PGR, comprising a major subgroup (74%) among infants, might successfully be treated with conventional therapy, whereas PPR require new therapeutic strategies, including early treatment intensification or bone marrow transplantation in first remission.

Prednisone Response Is the Strongest Predictor of Treatment Outcome in Infant Acute Lymphoblastic Leukemia

AbstractTo define prognostic factors in infant acute lymphoblastic leukemia (ALL), the outcome of 106 infants (age ≤12 months) during 3 consecutive multicenter trials of the Berlin-Frankfurt-Münster group (ALL-BFM 83, 86, and 90) was retrospectively analyzed according to presenting features and early in vivo response to prednisone. The prednisone response was defined as the cytoreduction (number of blood blasts per microliter at day 8) to a 7-day prednisone prephase and 1 intrathecal dose of methotrexate on day 1. Prednisone good responder (PGR; <1,000 blasts/μL) received conventional therapy and prednisone poor responder (PPR; ≥1,000 blasts/μL) received intensified therapy. Infant ALL was characterized by a high incidence of a white blood cell count greater than 100 × 103/μL (57%), central nervous system leukemia (24%), lack of CD10 expression (59%), 11q23 rearrangement (49%) including the translocation t(4;11) (29%), and a comparatively high proportion of PPR (26%), which were all significantly associated with inferior outcome by univariate analysis. The estimated probability for an event-free survival at 6 years (pEFS) was by far better for PGR compared with PPR, who had a dismal prognosis despite intensified treatment (pEFS, 53% ± 6%v 15% ± 7%, P = .0001). Infant PGR, who were less than 6 months of age (n = 40), lacked CD10 expression (n = 43), and/or had an 11q23 rearrangement (n = 17) fared significantly better compared with corresponding PPR, as indicated by a pEFS of 44% ± 8%, 49% ± 8%, and 41% ± 12%, respectively. In multivariate analysis, PPR was the strongest adverse prognostic factor (relative risk, 3.3; 95% confidence interval, 1.9 to 5.8; P< .0001). Infants with PGR, comprising a major subgroup (74%) among infants, might successfully be treated with conventional therapy, whereas PPR require new therapeutic strategies, including early treatment intensification or bone marrow transplantation in first remission.

Unrelated donor bone marrow transplantation for chronic myelogenous leukemia: a decision analysis.

Chronic myelogenous leukemia (CML) is an indolent but ultimately fatal disease. Because the natural history of CML varies and quality of life with CML may be excellent until shortly before death, deciding whether and when to pursue unrelated donor bone marrow transplantation is often difficult. To compare early transplantation, delayed transplantation, and no transplantation for patients with chronic-phase CML on the basis of discounted, quality-adjusted life expectancy. A markov model comparing different strategies was constructed. This model considers patient age, quality of life, risk aversion, and the competing risks for CML progression and transplant toxicity. Therapeutic decision at the time of diagnosis of CML. The base case is a 35-year-old patient with intermediate-prognosis CML. Younger and older patients with better and worse prognoses are also evaluated. Early transplantation, delayed transplantation, and no transplantation. Quality-adjusted, discounted life expectancy. For patients with newly diagnosed CML, transplantation within the first year provides the greatest quality-adjusted expected survival, although this benefit decreases with increasing patient age. For a 35-year-old patient with intermediate-prognosis CML, transplantation within the first year results in 53 more discounted, quality-adjusted years of life expectancy than does no transplantation. This finding is robust even with varying baseline assumptions. These results support the use of early unrelated donor bone marrow transplantation for most patients with CML.

Prognosis of children with chronic myeloid leukemia: a retrospective analysis of 75 patients

As the probability of survival of patients with chronic myelocytic leukemia (CML) gradually decreases over a period of 10 years, long-term follow-up is mandatory. Between 1977 and 1994, 68 children and adolescents between 1.0 and 18 years of age with CML in chronic phase and 7 presenting with blast crisis at diagnosis were reported to the study center in Münster. The Philadelphia-chromosome and/or BCR/ABL rearrangement could be detected in 66 children. The 4 Philadelphia-negative patients and 5 patients without karyotyping fulfilled the morphological criteria of CML. Clinical symptoms and hematological findings at presentations were similar to adult patients. Until 1985 chemotherapy consisted predominantly in busulfan (BU), later in hydroxyurea (HU) or a combination of both and since 1987 increasingly in HU plus interferon-alpha. 47 patients (6 in blast crisis) were allografted once or twice (n = 4) (27 HLA-identical, 16 unrelated, 4 haplo-identical) within 2.3-135 months (median 12 months) after diagnosis. 38 of 75 patients (3 in blast crisis at diagnosis) were alive after a median follow-up of 5.5 years. The probability of 12 years survival was 27%, SE 9% for patients in chronic phase. All deaths (n = 19) were leukemia-related in the 27 non-transplanted children. A comparison of survival for patients with or without bone-marrow transplantation (BMT) showed a significant difference in favour of the BMT-group (42%, SE 13% vs. 10%, SE 8%, p log-rank 0.003). The probability of survival increased to 62%, SE 10%, if patients transplanted later than 3 years after diagnosis were excluded. Only few patients (4/39 with information about the cause of death = 10%) died due to recurrent CML after BMT. Our data confirm the unfavourable outcome of CML in pediatric patients if treated with chemotherapy alone. With early BMT high cure rates can be achieved. If transplant-related mortality which in our patient group was 21% (8/39) can be reduced, even a higher cure rate appear realistic for the future.

Early autologous bone marrow transplantation (ABMT) in the treatment of Hodgkin's disease.

The use of ABMT "early" in Hodgkin's disease (HD) could refer to its to its application at diagnosis, as part of primary therapy or even at the first evidence of disease progression after primary therapy. We have recommended intensive therapy and ABMT to HD patients at the time of first relapse after a complete remission induced by primary chemotherapy. Among the 58 patients entering transplant protocols at the time of first relapse, the majority first received several cycles of conventional chemotherapy and/or local radiotherapy prior to hospitalization for conditioning and autotransplantation. However, all 58 were subsequently conditioned with high-dose cyclophosphamide, BCNU and VP 16-213 +/- cisplatin (CBV +/- P) and autologous transplantation. The progression free survival (PFS) after transplantation was 61% (95% confidence intervals [C.I.] 43%-74%) at a median follow-up of 3.6 (range 1.6-8.2) years. Two patients died of toxicity within the first 5 months of ABMT, while 3 late deaths occurred > 1 year post-transplant. The probability of progression was 28% (95% C.I. 17%-43%). Multivariate analysis identified 3 adverse risk factors for PFS-B symptoms at relapse, initial remission duration < 1 year and extranodal disease at relapse. PFS was significantly correlated with the number of adverse factors. Patients with 2 or 3 risk factors are candidates for more intensive or innovative measures due to the high relapse rate seen in these subgroups. Patients with 0 or 1 risk factors have a < 15% probability of relapse post-transplant, and are arguably candidates for less aggressive regimens.

Partial albinism with immunodeficiency (Griscelli syndrome)

Partial albinism with immunodeficiency is a rare and fatal immunologic disorder characterized by pigmentary dilution and variable cellular immunodeficiency. To define the phenotype, therapy, and outcome, we retrospectively analyzed seven consecutive patients. Primary abnormalities included a silvery-grayish sheen to the hair, large pigment agglomerations in hair shafts, and an abundance of mature melanosomes in melanocytes, with reduced pigmentation of adjacent keratinocytes. Clinical onset occurred between the ages of 4 months and 4 years and was characterized by accelerated phases (lymphohistiocytic infiltration of multiple organs, including the brain and the meninges), triggered by viral and bacterial infections. Characteristic laboratory features included pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and hypoproteinemia. Consistent immunologic abnormalities were characterized by absent delayed-type cutaneous hypersensitivity and impaired natural killer cell function. Some patients had secondary hypogammaglobulinemia, impaired major histocompatibility complex-mediated cytotoxic effects, a decreased capacity of lymphocytes to trigger a mixed lymphocyte reaction, or various functional granulocytic abnormalities. The disease seems to be invariably lethal without bone marrow transplantation; the mean age at the time of death was 5 years. Bone marrow transplantation has been performed in three cases; two patients died in the immediate posttransplantation period of infectious complications, but one patient is cured after a follow-up of 5 years. We conclude that partial albinism with immunodeficiency (Griscelli syndrome) can be differentiated from Chédiak-Higashi syndrome by pathognomonic histologic features. One of the underlying immunologic defects may be a defective function of natural killer cells, predisposing the patient to virus-associated hemophagocytic syndrome or accelerated phases. The prognosis is very poor unless early bone marrow transplantation is carried out. (J P EDIATR 1994;125:886-95)