The Cellular Basis of the Genetically Determined Hemopoietic Defect in Anemic Mice of Genotype Sl/Sld

The proliferation and function of hemopoietic cells derived from geneticallyanemic Sl/Sl^d mice have been studied by the use of cell transplantationtechnics. It was found that marrow cells derived from anemic Sl/Sl^d or Sl^d/Sl^dmice, when implanted into heavily irradiated mice of genotype +^sl/+^sl, arecapable of forming macroscopic spleen colonies, with approximately the samefrequency as cells derived from normal +^sl/+^sl mice. Marrow cells derivedfrom Sl/Sl^d animals were tested for their capacity to cure the anemia of W/W^rmice and were found to implant as rapidly and to have as long-lasting abeneficial effect as did marrow cells from +^sl/+^sl mice. The radiosensitivityof the colony-forming ability of marrow cells from Sl/Sl^d mice was found tobe similar to that found previously for +^sl/+^sl marrow cells, although theanemic animals are known to be more sensitive to total-body irradiation thanare their normal littermates. Marrow cells from +^sl/+^sl mice were found toproliferate more slowly in irradiated mice of genotype Sl/Sl^d than in irradiated+^sl/+^sl littermates, even when the anemic and the normal mice were joinedin parabiosis. These observations indicate that the hemopoietic colony-formingcells in mice of genotype Sl/Sl^d are normal, but fail to function adequately because the tissues of mice of this genotype are unable to provide sufficient support for proliferation and differentiation of these progenitor cells.

Submitted on November 25, 1964 Accepted on December 25, 1964     

Risk factors for syngeneic graft-versus-host disease after adult hematopoietic cell transplantation

Syngeneic graft-versus-host disease (sGVHD) has been described after hematopoietic cell transplantation (HCT) but remains poorly defined. We retrospectively reviewed adult syngeneic HCTs at our center (1980-2002) for sGVHD to investigate incidence, morbidity, and risk factors with a primary focus on parity. Among 119 transplantations, there were 21 cases of biopsy-proven sGVHD. The cumulative incidence was 18%, with multiorgan involvement in 6 cases and 1 death. sGVHD was more frequent when the donor was parous (32%) than nulliparous (9%) or male (13%; P = .03) and when the recipient was parous (31%) than nulliparous (7%) or male (13%; P = .02). Other univariable risk factors included older age (P < .01), busulfan/melphalan/thiotepa conditioning (P < .01), interleukin-2 (P = .02), HLA-A26 (P = .03), and more recent transplantation year (P < .01). Overall, risk factors were similar to those described in GVHD. Although an independent effect of parity could not be completely separated from other factors, donor and recipient pregnancy history merits further investigation.      

Aortic valve orifice equation independent of valvular flow intervals: application to aortic valve area computation in aortic stenosis and comparison with the Gorlin formula

An orifice equation is derived relating the effective aorticvalve area, A, the average aortic valve pressure gradient, dP,the stroke volume,SV, and the heart frequency, FH, through considerationsof momentum conservation across the aortic valve. This leadsto a formula consistent with Newton's second law of motion.The form of the new equation is A =(7.5 x 10^–5) SV F_H²/P_d, where A, V_s, F_H and P_d are expressed in cm², ml, s^–1and mmHg, respectively. Aortic valve areas computed with thenew orifice equation are found to correlate with those computedby the Gorlinformula in conditions of resting haemodynamic statesat a level of r = 0.86, SE=0.25 cm², N= 120. The results suggestthat the new formula may be considered as an independent orificeequation having a similar domain of validity as the Gorlinformula.The new equation offers the possibility of deriving additionaluseful haemodynamic relationships through combination with establishedcardiological formulas and applying it in a noninvasive Dopplerultrasonic or echocardiographic context.     

High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study

BAALC expression is considered an independent prognostic factor in cytogenetically normal acute myeloid leukemia (CN-AML), but has yet to be investigated together with multiple other established prognostic molecular markers in CN-AML. We analyzed BAALC expression in 172 primary CN-AML patients younger than 60 years of age, treated similarly on CALGB protocols. High BAALC expression was associated with FLT3-ITD (P = .04), wild-type NPM1 (P < .001), mutated CEBPA (P = .003), MLL-PTD (P = .009), absent FLT3-TKD (P = .005), and high ERG expression (P = .05). In multivariable analysis, high BAALC expression independently predicted lower complete remission rates (P = .04) when adjusting for ERG expression and age, and shorter survival (P = .04) when adjusting for FLT3-ITD, NPM1, CEBPA, and white blood cell count. A gene-expression signature of 312 probe sets differentiating high from low BAALC expressers was identified. High BAALC expression was associated with overexpression of genes involved in drug resistance (MDR1) and stem cell markers (CD133, CD34, KIT). Global microRNA-expression analysis did not reveal significant differences between BAALC expression groups. However, an analysis of microRNAs that putatively target BAALC revealed a potentially interesting inverse association between expression of miR-148a and BAALC. We conclude that high BAALC expression is an independent adverse prognostic factor and is associated with a specific gene-expression profile.      

Calcitonin receptor-like receptor guides arterial differentiation in zebrafish

The calcitonin receptor-like receptor (crlr) is a major endothelial cell receptor for adrenomedullin, a peptide vasodilator involved in cardiovascular development, homeostasis, and disease. Here, we used the zebrafish (Danio rerio) model to characterize the role of crlr in vascular development. Crlr is expressed within somites from the 4- to the 13-somite stage and by arterial progenitors and axial vessels during zebrafish development. Loss of crlr results in profound alterations in vascular development and angiogenesis, including atrophic trunk dorsal aorta and interruption of anterior aortic bifurcation, delay in intersomitic vessel development, and lack of blood circulation. Remarkably, crlr morphants are characterized by the loss of arterial endothelial cell identity in dorsal aorta, as shown by the lack of expression of the arterial markers ephrin-B2a, DeltaC, and notch5. Down-regulation of crlr affects vascular endothelial growth factor (vegf) expression, whereas vegf overexpression is sufficient to rescue arterial differentiation in crlr morphants. Finally, genetic and biochemical evidences indicate that somitic crlr expression is under the control of sonic hedgehog. These data demonstrate that crlr plays a nonredundant role in arterial differentiation, representing a novel element of the sonic hedgehog–vegf-notch signaling cascade that controls arterial/venous fate.      

Modulation of murine embryonic stem cell-derived CD41+c-kit+ hematopoietic progenitors by ectopic expression of Cdx genes

Cdx1, Cdx2, and Cdx4 comprise the caudal-like Cdx gene family in mammals, whose homologues regulate hematopoietic development in zebrafish. Previously, we reported that overexpression of Cdx4 enhances hematopoietic potential from murine embryonic stem cells (ESCs). Here we compare the effect of ectopic Cdx1, Cdx2, and Cdx4 on the differentiation of murine ESC-derived hematopoietic progenitors. The 3 Cdx genes differentially influence the formation and differentiation of hematopoietic progenitors within a CD41⁺c-kit⁺ population of embryoid body (EB)–derived cells. Cdx1 and Cdx4 enhance, whereas Cdx2 strongly inhibits, the hematopoietic potential of CD41⁺ckit⁺ EB-derived cells, changes that are reflected by effects on hematopoietic lineage-specific and Hox gene expression. When we subject stromal cell and colony assay cultures of EB-derived hematopoietic progenitors to ectopic expression of Cdx genes, Cdx4 dramatically enhances, whereas Cdx1 and Cdx2 both inhibit hematopoietic activity, probably by blocking progenitor differentiation. These data demonstrate distinct effects of Cdx genes on hematopoietic progenitor formation and differentiation, insights that we are using to facilitate efforts at in vitro culture of hematopoietic progenitors from ESC. The behavior of Cdx genes in vitro suggests how derangement of these developmental regulators might contribute to leukemogenesis.      

High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated

Inappropriate expression of EVI1 (ecotropic virus integration-1), in particular splice form EVI1-1D, through chromosome 3q26 lesions or other mechanisms has been implicated in the development of high-risk acute myeloid leukemia (AML). To validate the clinical relevance of EVI1-1D, as well as of the other EVI1 splice forms and the related MDS1/EVI1 (ME) gene, real-time quantitative polymerase chain reaction was performed in 534 untreated adults with de novo AML. EVI1-1D was highly expressed in 6% of cases (n = 32), whereas 7.8% were EVI1⁺ (n = 41) when all splice variants were taken into account. High EVI1 predicted a distinctly worse event-free survival (HR = 1.9; P = .002) and disease-free survival (HR = 2.1, P = .006) following multivariate analysis. Importantly, we distinguished a subset of EVI1⁺ cases that lacked expression of ME (EVI1⁺ME^–; n = 17) from cases that were ME⁺ (EVI1⁺ME⁺; n = 24). The atypical EVI1⁺ME^– expression pattern exhibited cytogenetically detectable chromosomal 3q26 breakpoints in 8 cases. Fluorescence in situ hybridization revealed 7 more EVI1⁺ME^– cases that carried cryptic 3q26 breakpoints, which were not found in the EVI1⁺ME⁺ group. EVI1⁺ME^– expression predicts an extremely poor prognosis distinguishable from the general EVI1⁺ AML patients (overall survival [OS]: P < .001 and event-free survival [EFS]: P = .002). We argue that EVI1/ME quantitative expression analysis should be implemented in the molecular diagnostic procedures of AML.     

POLYMYALGIA RHEUMATICA IS ASSOCIATED WITH BOTH HLA-DRB1*0401 and DRBl*0404

The frequency of HLA-DRB1 alleles was determined in 68 Caucasoidpatients with polymyalgia rheumatica (PMR) and 140 controlsusing polymerase chain reaction (PCR) sequence-specific oligonucleotidetyping. In keeping with previous studies, an increased frequencyof DRB1^*04 was observed in patients [55.9% vs 35.0%, odds ratio(OR) 2.4, 95% confidence interval (CI) 1.3–4.4]. HLA-DRBl^*0101frequency was also increased in patients, although less confidencecould be placed on this association (19.1% vs 14.3%, OR 1.4,95%CI 0.6–3.3). HLA-DRB1^*O4 subtyping indicated that thefrequencies of both DRB1^*0401 (38.2% vs 22.1%, OR 2.2, 95% CI1.0–4.3) and DRB1^*0404 (16.2% vs 5.0%, OR 3.7, 95% CI1.2–11.1) were specifically raised. An increased frequencyof the RA shared epitope (QKRAA/QRRAA) was also observed inthis group (75.0% vs 44.2%, OR 3.8, 95% CI 1.9–7.6). Whenthe analysis was restricted to only DRB1^*04-negative patientsand controls, the frequencies of DRB1^*0301, ^*11 and ^*08 weremarginally raised. However, no obvious relationship appearedto exist between PMR susceptibility and DRB1 alleles carryingthe DYF conserved epitope in the second hypervariable region.Autoantibodies to thyroid antigens were present in 23% of patients.An increased frequency of DRBl^*0301 was observed in patientswith thyroid microsomal antibodies compared to those without(54.5% vs 24.6%, OR 3.7, 95% CI 0.8–17.0). This increasewas not observed in patients with thyroglobulin autoantibodies.These data indicate that both DRB 1^*0401 and ^*0404 are associatedwith PMR, and that this may extend to include DRB1^*0101. Theimmunogenetic profile of susceptibility markers in this conditionappears to be similar to that in rheumatoid arthritis. KEY WORDS: Polymyalgia rheumatica, HLA-DR4, Thyroid antibodies     

Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia

The outcome for adult patients with BCR-ABL–positive acute lymphoblastic leukemia (ALL) remains dismal and long-term survival can hardly be achieved except by allogeneic hematopoietic stem cell transplantation (HSCT). The Japan Adult Leukemia Study Group (JALSG) has recently started a phase 2 trial with intensive chemotherapy and imatinib for newly diagnosed BCR-AB–positive ALL patients, and we present here the interim results for the first 24 patients. All patients except one case of early death (96%) attained complete remission (CR) after a single course of remission induction therapy. Polymerase chain reaction (PCR) negativity was achieved in 28% of the patients on day 28, in 50% on day 63, and in up to 78% during the follow-up period. The toxicity profile was almost similar to that with chemotherapy alone. As a result, 15 patients (63%) could receive an allogeneic HSC transplant during their first CR. Although the number of patients is small and the observation period is too short, the combination therapy is very promising and produces high-quality CR for most newly diagnosed patients with BCR-ABL–positive ALL. This is especially useful because it provides the patients with a better chance to receive an allogeneic HSC transplant.      

Increased cardiac sympathetic nervous activity in patients with unstable coronary heart disease

We have evaluated overall and cardiac sympathetic activity in47 patients undergoing coronary angiography, 27 with stableangina of at least 3 months duration, and 20 with unstable ischaemicsymptoms within this period. Cardiac and overall sympatheticactivity were assessed using radiotracer noradrenaline kinetictechniques to measure cardiac and total noradrenaline spilloverto plasma. Overall sympathetic activity (whole body noradrenaline spillover)was similar in the two groups, whereas cardiac sympathetic activity(cardiac noradrenaline spillover) was strikingly increased inthe patients with unstable ischaemic symptoms (102 ±23 pmol . min^–1 vs 34 ± 4 pmol . min^–1, P< 0.001), as was the cardiac to whole body noradrenalinespillover ratio (0.043 ± 0.008 vs 0.021± 0.005,P < 0.01). Coronary sinus bloodflow (50 ± 4 ml . min^–1vs 38 ± 4 ml . min^–1 P < 0.05) and coronarysinus noradrenaline concentration (2.60±0.38 nmol . 1^–1vs 1.41±0.17 nmol . 1^–1, P<0.01) were also increasedin the patients with unstable ischaemic syndromes. Left ventricularejection fraction was similar in the two groups (63 ±2% vs 62 ± 2%). Patients with unstable ischaemic symptoms within the previousthree months have increased cardiac sympathetic nervous activitycompared to patients with stable angina. This may in part explainwhy patients with unstable ischaemic syndromes are at increasedrisk of sudden cardiac death.     

Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial

The standard initial therapy for acute graft-versus-host disease (GVHD) is corticosteroids. Daclizumab is a humanized monoclonal antibody against the interleukin 2 (IL-2) receptor expressed on activated T lymphocytes. Because of daclizumab's favorable toxicity profile and response rate in steroid-resistant GVHD, a multicenter, double-blinded, randomized study of corticosteroids with or without daclizumab for initial treatment of acute GVHD was conducted. A total of 102 evaluable subjects of the targeted 166 were enrolled at 5 participating sites. Methylprednisolone at a dose of 2 mg/kg or daily equivalent was given in conjunction with daclizumab 1 mg/kg or placebo on study days 1, 4, 8, and weekly as long as clinically indicated. The groups were balanced for clinical characteristics. GVHD response rates by study day 42 were similar (53% vs 51%; P = .85). The study was halted after a planned interim analysis showed a significantly worse 100-day survival in the group receiving corticosteroids plus daclizumab (77% vs 94%; P = .02). Overall survival at 1 year was also inferior in the combination arm (29% vs 60%; P = .002). Both relapse- and GVHD-related mortality contributed to the increased mortality in the combination group. The combination of corticosteroids and daclizumab should not be used as initial therapy of acute GVHD.      

p16INK4A tumor suppressor gene expression and CD3epsilon deficiency but not pre-TCR deficiency inhibit TAL1-linked T-lineage leukemogenesis

Inactivation of the CDKN2 genes that encode the p16^INK4A and p14^ARF proteins occurs in the majority of human T-cell acute lymphoblastic leukemias (T-ALLs). Ectopic expression of TAL1 and LMO1 genes is linked to the development of T-ALL in humans. In TAL1xLMO1 mice, leukemia develops in 100% of mice at 5 months. To identify the molecular events crucial to leukemic transformation, we produced several mouse models. We report here that expression of P16^INK4A in developing TAL1xLMO1 thymocytes blocks leukemogenesis in the majority of the mice, and the leukemias that eventually develop show P16^INK4A loss of expression. Events related to the T-cell receptor ß selection process are thought to be important for leukemic transformation. We show here that the absence of the pT chain only slightly delays the appearance of TAL1xLMO1-induced T-ALL, which indicates a minor role of the pT chain. We also show that the CD3-mediated signal transduction pathway is essential for this transformation process, since the TAL1xLMO1xCD3-deficient mice do not develop T-ALL for up to 1 year.      

Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post-germinal center leukemogenic selection

We examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 63 (2.6%) expressed immunoglobulin (Ig) encoded by the Ig heavy-chain-variable-region gene (IGHV), IGHV3-21. We identified the amino acid sequence DANGMDV (motif-1) or DPSFYSSSWTLFDY (motif-2) in the Ig heavy-chain (IgH) third complementarity-determining region (HCDR3) of IgH, respectively, used by 25 or 3 cases. The IgH with HCDR3 motif-1 or motif-2, respectively, was paired with Ig light chains (IgL) encoded by IGLV3-21 or IGKV3-20, suggesting that these Ig had been selected for binding to conventional antigen(s). Cases that had HCDR3 motif-1 had a median time from diagnosis to initial therapy comparable with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21/IGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor editing and after germinal-center leukemogenic selection.      

Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders

To study the prevalence of the Val617Phe JAK2 mutation in familial cases of myeloproliferative disorder (MPD) and its possible implication as a predisposing genetic factor, we analyzed 72 families including 174 patients (81 polycythemia vera [PV], 68 essential thrombocythemia [ET], 11 myelofibrosis with myeloid metaplasia [MMM], 12 chronic myeloid leukemia), 1 systemic mastocytosis, and 1 chronic myelomonocytic leukemia (CMML). The JAK2 mutation was found in three quarters of patients with PV and MMM and in half of patients with ET. Among 46 families with at least 2 cases of PV, ET, or MMM, the JAK2 mutation was absent in 6 families, heterogeneously distributed in 18, and present in all MPD patients in 22. Among these 22 families, the absence of the JAK2 mutation both in purified T and B cells in 13 unrelated patients and the observation of variable ratios of the JAK2 mutant allele in patient leucocytes indicated that the Val617Phe JAK2 mutation was acquired in familial MPDs. The JAK2 mutation was present in natural killer cells in two thirds of tested patients (27 of 40), suggesting its occurrence in a multipotent hematopoietic progenitor cell. The analysis of the hematologic profile showed that the homozygous JAK2 mutation confers a proliferative advantage and is associated with the progression of the hematologic disease. (Blood. 2006;108:346-352)      

Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis

Splenic marginal zone lymphoma (SMZL) is a newly recognized lymphoma type whose precise molecular pathogenesis is still essentially unknown. This hampers differential diagnosis with other small B-cell malignancies. With the aim of characterizing this tumor more comprehensively, and of identifying new diagnostic and prognostic markers, we performed cDNA microarray expression profiling and tissue microarray (TMA) immunohistochemical studies in a relatively large series of 44 SMZLs. The results were related to immunoglobulin heavy chain variable region (IgV_H) mutational status and clinical outcome. SMZLs display a largely homogenous signature, implying the existence of a single molecular entity. Of the genes deregulated in SMZLs, special mention may be made of the genes involved in B-cell receptor (BCR) signaling, tumor necrosis factor (TNF) signaling and nuclear factor-B (NF-B) activation, such as SYK, BTK, BIRC3, TRAF3, and LTB. Other genes observed were SELL and LPXN, which were highly expressed in spleen, and lymphoma oncogenes, such as ARHH and TCL1. In contrast, the genes CAV1, CAV2, and GNG11 located in 7q31, a commonly deleted area, were down-regulated in the entire series. A comparison with the genes comprising the signature of other small B-cell lymphomas identified 3 genes whose expression distinguishes SMZL, namely ILF1, SENATAXIN, and CD40. Shorter survival was associated with CD38 expression, naive IgV_H genes, and the expression of a set of NF-B pathway genes, including TRAF5, REL, and PKCA. (Blood. 2005;106:1831-1838)      

Cost effectiveness of neonatal ECG screening for the long QT syndrome.

We read with interest the recent article by Quaglini et al.¹in the European Heart Journal, concerning cost efficacy of proposedneonatal ECG screening for long QT syndrome. We all agree thatundiagnosed cases of LQTS likely play a role of as yet undeterminedmagnitude in sudden death in very young children, includingsudden infant death syndrome. A similar study has been previouslypublished.² We have some     

The JAK2 617V>F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera

The JAK2 617V>F mutation is frequent in polycythemia vera (PV) and essential thrombocythemia (ET). Using quantitative polymerase chain reaction (PCR), we found that high levels of JAK2 617V>F in PV correlate with increased granulocytes and high levels of hemoglobin and endogenous erythroid colony formation. We detected normal progenitors and those that were heterozygous or homozygous for the mutation by genotyping ET and PV clonal immature and committed progenitors. In PV patients, we distinguished homozygous profiles with normal, heterozygous, and homozygous progenitors from heterozygous profiles with only heterozygous and normal progenitors. PV patients with a heterozygous profile had more mutated, committed progenitors than did other PV and ET patients, suggesting a selective amplification of mutated cells in the early phases of hematopoiesis. We demonstrated that mutated erythroid progenitors were more sensitive to erythropoietin than normal progenitors, and that most homozygous erythroid progenitors were erythropoietin independent. Moreover, we observed a greater in vitro erythroid amplification and a selective advantage in vivo for mutated cells in late stages of hematopoiesis. These results suggest that, for PV, erythrocytosis can occur through two mechanisms: terminal erythroid amplification triggered by JAK2 617V>F homozygosity, and a 2-step process including the upstream amplification of heterozygous cells that may involve additional molecular events.      

Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis

Rituximab, an anti-CD20 monoclonal antibody, has been used to treat autoimmune disorders such as mixed cryoglobulinemia (MC). However, its mechanisms of action as well as the effects on cellular immunity remain poorly defined. We investigated the changes of peripheral blood B- and T-cell subsets, the clonal VH1–69 cells, as well as the cytokine profile following rituximab therapy. The study involved 21 patients with hepatitis C–related MC who received rituximab, of whom 14 achieved a complete response. Compared with healthy and hepatitis C virus (HCV) controls, pretreatment abnormalities in MC patients included a decreased percentage of naive B cells (P < .05) and CD4⁺CD25⁺FoxP3⁺ regulatory T cells (P = .02) with an increase in memory B cells (P = .03) and plasmablasts (P < .05). These abnormalities were reverted at 12 months after rituximab. Clonal VH1–69⁺ B cells dramatically decreased following treatment (32% ± 6% versus 8% ± 2%, P = .01). Complete responders of rituximab exhibited an expansion of regulatory T cells (P < .01) accompanied with a decrease in CD8⁺ T-cell activation (P < .01) and decreased production of interleukin 12 (IL-12; P = .02) and interferon- (IFN-; P = .01). Our findings indicate that in patients with MC, response to B-cell depletion induced by rituximab effectively normalizes many of the disturbances in peripheral B- and T-lymphocyte homeostasis.      

Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research

The best treatment approach for children with B-precursor acute lymphoblastic leukemia (ALL) in second clinical remission (CR) after a marrow relapse is controversial. To address this question, we compared outcomes in 188 patients enrolled in chemotherapy trials and 186 HLA-matched sibling transplants, treated between 1991 and 1997. Groups were similar except that chemotherapy recipients were younger (median age, 5 versus 8 years) and less likely to have combined marrow and extramedullary relapse (19% versus 30%). To adjust for time-to-transplant bias, treatment outcomes were compared using left-truncated Cox regression models. The relative efficacy of chemotherapy and transplantation depended on time from diagnosis to first relapse and the transplant conditioning regimen used. For children with early first relapse (< 36 months), risk of a second relapse was significantly lower after total body irradiation (TBI)–containing transplant regimens (relative risk [RR], 0.49; 95% confidence interval [CI] 0.33-0.71, P < .001) than chemotherapy regimens. In contrast, for children with a late first relapse ( 36 months), risks of second relapse were similar after TBI-containing regimens and chemotherapy (RR, 0.92; 95% CI, 0.49-1.70, P = .78). These data support HLA-matched sibling donor transplantation using a TBI-containing regimen in second CR for children with ALL and early relapse.      

The Threshold Dose of P32 for Leukemic Cells of the Lymphocytic and Granulocytic Series

Analyses of the threshold dose of P³² to control 201 chronic lymphocyticleukemia patients and 100 chronic granulocytic leukemia patients and of theP³² dose to maintain 133 chronic lymphocytic leukemia patients for a meanperiod of 50.2 months and 49 chronic granulocytic leukemia patients for amean period of 33.6 months are analyzed. These threshold doses fit the logarithmic probability distributions given in the tables and figures.

See PDF for Figure

See PDF for Figure

When the dose in mc. to control was plotted against the leukocyte count,a straight line was obtained on log log paper. The equation for this curvefor the median dose to control chronic granulocytic leukemia is: log mc. P³²per 12 weeks = 0.33 log L - 0.633, where L is the leukocyte count on theday the first P³² was given. The equation for the log log curve relating mediandose to control chronic lymphocytic leukemia to initial counts above 15,000is: log mc. P³² per 12 weeks = 0.47 log L - 1.420. But the 40 aleukemic orsubleukemic cases with leukocyte counts below 15,000 had a median P³² requirement and standard deviation that did not differ significantly from thatfor the entire group, suggesting that this subleukemic group includes patientsresembling the entire spectrum of cases with elevated initial leukocyte counts.

See PDF for Figure

See PDF for Figure

The median dose of P³² per year to maintain chronic granulocytic leukemiacases fits the equation: log P³² per year = 0.546 log L - 1.506, and the corresponding equation for chronic leukemic lymphocytic leukemia is: log mc.P³² per year = 0.45 log L - 1.22. The group of lymphocytic leukemias withinitial counts below 15,000 again showed a median and distribution similar tothat for the entire leukemic group.

The remarkable fact that the dose requirement years later is related to theinitial leukocyte count is discussed. Revised recommendations on dosageschedule for titrated, regularly spaced P³² therapy of the chronic leukemiasare presented.

For each individual patient with chronic leukemia, there is a thresholddose of intravenously administered P³² below which no effect is observed. Thedose and interval which will maintain a uniform leukocyte count of about15,000 may remain unchanged for years or may show abrupt changes at anytime to either a lower or higher requirement.

Submitted on November 6, 1959 Accepted on January 4, 1960