Ruth Vogel

Successful non‐neurotoxic therapy (without radiation) of a multifocal primary brain lymphoma with a methotrexate, vincristine, and BCNU protocol (DEMOB)

A 3.5‐year‐old boy with a multifocal primary lymphoma of the brain was treated successfully without neurotoxicity with a treatment regimen that did not include radiation. The protocol of Dexacort (dexamethasone), methotrexate, Oncovin (vincristine), and BCNU (carmustine) (DEMOB), which was developed with the use of MTX pharmocokinetic studies, was given over 7.5 months, and resulted in tumor disappearance on computerized tomography scans and marked improvement in clinical status. The patient remains in good health 3 years after diagnosis (March 1985).

Immunologic dysregulation in a patient with familial hemophagocytic lymphohistiocytosis

A 6‐year‐old Jewish Iranian girl with familial hemophagocytic lymphohistiocytosis (FHLH) is described. The course of the disease fluctuated with partial initial response to antibiotics, steroids, and supportive treatment. Subsequent cytotoxic treatment, including VP‐16, Velban (vinblastine sulfate), and methotrexate (MTX) controlled the disease for a few months but the child died with a clinical picture of meningocephalitis 1.5 years later. Benign‐looking lymphohistiocytic infiltrates with varying degrees of hemophagocytosis were present in the bone marrow, pleural effusion, cerebrospinal fluid (CSF), liver, and brain. Clinical and laboratory evidence of immunologic dysregulation during the disease could be demonstrated. Frequent and intense viral and bacterial infectious diseases were encountered. The laboratory examination most consistently found was the absence of natural killer (NK) cell activity against K562 target cells. The impaired activity of NK cells persisted during all stages of the disease including remission, although NK cell numbers, determined morphologically and immunophenotypically (by Leu‐11, Leu‐7), were normal. Natural killer activity could not be restored by interferon. Moreover, the interferon system appeared to be intact. Impaired monokin interleukin 1 (IL‐I) production by peripheral blood monocytes was found and cound not be restored by indomethacin. Lymphopenia, a mild decrease in T4 numbers, and subsequently, decreased proliferative response to mitogens was noted. Elevated immunoglobulin levels were found during exacerbations and viral episodes, at times accompanied by the presence of auto‐antibodies. The exaggerated fatal lymphohistiocytic response typical for FHLH could be attributed to a underlying genetic pathologic dysregulation of the various immunological response pathways.

Biologic and cytogenetic characteristics of leukemia in infants

Clinical features, leukemic cell characterization, chromosomal findings, and treatment outcome were analyzed in a retrospective study of 30 cases with acute leukemia of infancy, 24 infants with acute lymphoblastic leukemia (ALL), and six cases with acute nonlymphoblastic leukemia (ANLL). Extensive bulky disease with organomegaly, central nervous system (CNS), and skin involvement were prominent features at diagnosis with a higher frequency in ANLL as compared to ALL. Four of six ANLL patients were classified as monocytic or myelomonocytic. In the ALL group nine of 24 (36%) were non‐L1 morphology and six of 17 (33%) were common ALL antigen (CALLA) negative, the majority of them (five of six) were included in the non‐L1 group. Immunophenotyping revealed four cases with early B‐cell (three patients: Ia+B4+, and one patient: Ia+) and two cases with T‐cell. Mixed lineage leukemia was found in five infants. Heavy chain immunoglobulin gene rearrangement was present in six cases tested, two CALLA+, two with Ia+B4+, and two were undifferentiated mixed lineage leukemia. Chromosomal aberrations were detected in ten of 18 patients, mostly in ANLL and CALLA negative ALL. Translocations were detected in six patients, involving 4q21‐23 and 11q23 in three and two cases, respectively. The probability of five‐year DFS was 27% for the whole group. The worst prognosis was observed in infants younger than 6 months of age, in whom the leukemia cell characteristics was compatible with stem cell: ANLL, very early pre‐B, or undifferentiated mixed type. The chromosomal aberrations found in all cases included translocation with the seemingly nonrandom breakpoints at 4q21 and 11q23, and breakpoints that corresponded to known fragile sites. This finding may be suggestive of an underlying genetic predisposition associated with the poor prognosis of leukemia of infancy.

Leukemia of early infancy. Early B-cell lineage associated with t(4:11).

A case of infantile acute leukemia associated with translocation t(4:11)(q21:q23) is reported. This leukemia has a very poor prognosis, and this patient survived for only 9 months. The blast cell morphology was L1/L2 according to the FAB classification and showed a lymphoid appearance on transmission electron microscopy. The histochemical stains showed a pattern of periodic acid‐Schiff positivity and variable alpha‐naphtyl acetate staining. The cells were TdT‐positive and surface‐marker phenotyping was positive for Ia‐like and B4 antigens but negative for CALLA, T‐cell markers, myelocyte and monocyte markers. The leukemic cells represent a frozen state of a very early precursor, corresponding to the earliest recognizable stage of the B‐cell lineage. This observation may contribute to the controversion regarding the cell origin of this unique leukemia associated with t(4:11), lymphatic versus null cell, early myeloid, or mixed, and points to the possibility of a very early B‐cell lineage leukemia.

Involvement of 11p15 and 3q21q26 in therapy-related myeloid leukemia (t-ML) in children: Case reports and review of the literature☆

The cytogenetic findings of therapy-related myeloid leukemia (t-ML) in three children are presented. These included one male patient with acute lymphoblastic leukemia (ALL) who underwent bone marrow transplantation and developed therapy-related myeloproliferative disease (t-MPD) in the female-donor hematopoietic cells 2.5 years after receiving radiation and epipodophyllotoxin therapy for ALL testicular relapse. Bone marrow leukemic cell karyotype revealed 46,XX,add (11)(p15) and a normal female karyotype in the peripheral blood lymphocytes. The other two children, one with ALL and one with ganglioneuroblastoma, developed fatal t-MPD and therapy-related acute myeloblastic leukemia (t-AML) preceded by myelodysplastic syndrome (t-MDS), respectively, 5 years after diagnosis, following administration of alkylating agents and irradiation. Monosomy 7 was present in both, and was combined with inv(3)(q21q26) in the second patient. Our review of the cytogenetic findings in 91 previously reported pediatric patients with t-ML suggested that the involvement of 11p15 and 3q21-->23, 3q24-q26 with or without a combination of translocation 11q23 and -7/7q-, respectively, are nonrandom aberrations of t-ML in children. Comparison of the chromosomal changes in t-ML between the pediatric and an adult series revealed some differences which may result from differences in treatment modalities and which, in addition, may indicate a possible role of genetic and/or age-dependent factors in the pathogenesis of therapy-related leukemogenesis in children.

Methotrexate-Induced Leukoencephalopathy is Treatable with High-Dose Folinic Acid: A Case Report and Analysis of the Literature

An episode of leukoencephalopathy is reported in a 13-year-old girl who, after standard radiotherapy for a posterior fossa medulloblastoma, received 8 treatments with a protocol containing a 4-hour infusion of 500 mg/m2 methotrexate and 12 mg intrathecal methotrexate. The leukoencephalopathy, documented clinically and by CT and EEG, cleared after 2350 mg of leucovorin (citrovorum factor, folinic acid) was given in addition to the 135 mg given as part of the therapy. A review of the literature suggests that leukoencephalopathy may be prevented by high doses of leucovorin and can be treated by high doses, if lower doses were used initially. When high dose leucovorin was not used, residual neurological damage is not unusual.

Room temperature ADP induced first stage hyperaggregation of human blood platelets: a previously undescribed phenomenon and its relationship to spontaneous cold induced platelet aggregation

ADP induced human platelet aggregation was shown to be accentuated when tested at 20‐30°C as increased sensitivity and as a greater change of optical density although second stage aggregation and the release reaction did not occur. This previously undescribed phenomenon is defined as room temperature ADP induced first stage hyperaggregation. Aggregation, which occurs under the above mentioned conditions with a quantity of ADP insufficient to maintain the aggregation (usually less than 1 5 μm), is reversible when the temperature is raised to 3 7°C. After rewarming to these temperatures, second stage aggregation appeared in the presence of larger quantities of ADP (usually more than 2 μm) and could be blocked by aspirin. The absence of the release reaction was demonstrated with a lumi‐aggregometer. Spontaneous cold induced platelet aggregation seen after chilling platelets to 0‐4°C is shown to be a distinct phenomenon.

Poor Prognosis in Childhood Acute Lymphoblastic Leukemia (ALL) Is Associated with HLA-A11

Acute childhood lymphoblastic leukemias (ALL) consists of several biologically distinct malignancies derived from different ancestral cells. A number of clinical and hematologic parameters are currently considered to be indicators of poor prognosis, i.e., male sex, high whiteblood cell counts, age below 2 or over 10 years, the presence of certain karyotypic abnormalities, and cell surface markers (1–3).