Autoimmune sequence of streptococcal M protein shared with the intermediate filament protein, vimentin.

The crossreactivity of antibodies against a renal autoimmune epitope of Streptococcus pyogenes M protein with glomerular mesangial cells was investigated. The antibodies directed against the amino acid sequence Ile-Arg-Leu-Arg of the nephritogenic type 1 M protein reacted in a fibrillar pattern with mesangial cells cultured from isolated glomeruli. In Western blots of urea-extracted mesangial proteins, the antibodies reacted with a 56-kD protein. Monoclonal and polyclonal antibodies identified the 56-kD mesangial protein as vimentin. Two synthetic peptides of human vimentin containing the sequence Arg-Leu-Arg reacted with the autoimmune antibodies raised against a streptococcal M protein peptide. These results provide evidence that the intermediate filament protein vimentin shares autoimmune epitopes with streptococcal M protein.

Lumbar puncture and subdural hygroma and hematomas in hematopoietic cell transplant patients.

We reviewed records of hematopoietic cell transplantation (HCT) patients seen over the past 10 years who had head scan documentation of subdural fluid collections. A total of 17 patients were identified: 13 with allogeneic and 4 with autologous HCT (0.71% of allogeneic and 0.13% of autologous HCT patients seen in this time interval). Although less than 20% of HCT patients have lumbar puncture, 8 of the 17 subdural patients had lumbar puncture. The lumbar puncture was done 5-112 days (median 46 days) before subdural detection. Acute lymphocytic leukemia was the diagnosis in five of these eight; whereas, either acute myelogenous leukemia or myelodysplasia was the diagnosis in seven of the nine patients without lumbar puncture. In the patient group with lumbar puncture, subdurals were diagnosed earlier after HCT (median 25 days versus 5 months in the patient group without lumbar puncture) and were more often hygromas (37.5 versus 0%). These results support the suggestion of lumbar puncture or intrathecal therapy as a risk factor for subdurals. The presumptive mechanism involves lumbar cerebrospinal leak, low intracranial pressure, downward displacement of the brain, cerebrospinal fluid accumulation into the inner dural layers of the cerebral convexities (hygromas) and bleeding into these fluid collections (hematomas).

Bone marrow transplantation for hematologic malignancies in patients aged 30 years or older.

During the past 10 years, 86 patients 30 to 54 years of age with hematologic malignancies were prepared with high-dose radiochemotherapy and received histocompatible bone marrow grafts. Thirty-four of these patients are surviving for 4 months to 9 years (median, 26 months) following marrow transplantation and 32 of them are in continuing complete remission (CR). Disease-free survival is 44% for 37 patients who were in first remission of acute leukemia or in the chronic phase of chronic granulocytic leukemia (CGL), 23% for 39 patients whose leukemia had relapsed at least once before transplantation or who had advanced stages of CGL, and 60% for ten patients who had hematologic malignancies other than leukemia. The median age of the surviving 34 patients is 36 years (range, 30 to 43 years). The incidence of moderate to severe acute graft-v-host disease (GVHD) was 48% and of chronic GVHD, 26%. The major causes of failure were interstitial pneumonia in 31 patients (24 of whom had antecedent acute GVHD) and recurrent leukemia in 12 patients (11 of whom had either never entered a CR or had relapsed at least once with acute leukemia or had progressive CGL before transplantation). Our data warrant further prospective studies in patients with hematologic malignancies who are older than 30 years.

High-dose therapy followed by autologous peripheral-blood stem-cell transplantation for patients with Hodgkin's disease and non-Hodgkin's lymphoma using unprimed and granulocyte colony-stimulating factor-mobilized peripheral-blood stem cells.

PURPOSE: To evaluate (1) the effect of granulocyte colony-stimulating factor (G-CSF) on peripheral-blood stem-cell (PBSC) mobilization; (2) the rate of hematopoietic recovery after G-CSF-mobilized PBSC transplantation; and (3) the outcome of high-dose myeloablative therapy and PBSC transplantation in patients with relapsed or refractory lymphoma. PATIENTS AND METHODS: Ninety-five patients with lymphoma underwent high-dose therapy followed by PBSC transplant in three sequentially treated cohorts of patients in a nonrandomized study. The first 30 patients received nonmobilized PBSCs (unprimed) without G-CSF after transplant, the next 26 patients received PBSC that were mobilized with G-CSF 5 micrograms/kg/d (primed-5) plus G-CSF after transplant, and the last 39 patients received PBSC mobilized by G-CSF 10 micrograms/kg/d (primed-10) plus G-CSF after transplant. The conditioning regimen consisted of fractionated total-body irradiation (FTBI) 12 Gy in combination with etoposide 60 mg/kg and cyclophosphamide 100 mg/kg. Patients with prior radiotherapy received carmustine (BCNU) 450 mg/m2 instead of FTBI. RESULTS: The use of G-CSF-mobilized PBSCs in combination with G-CSF posttransplant resulted in a significantly accelerated time to recovery of both granulocyte and platelet when compared with the unprimed group. The median number of days to an absolute granulocyte count (ANC) of greater than 0.5 x 10(9)/L was 10 days for G-CSF primed versus 20 days for the unprimed (P = .0001). The median days to platelet transfusion independence was 16 and 31 days (P = .0001) for the G-CSF primed and unprimed, respectively. There were also significant reductions in the number of platelet (P = .02) and RBC transfusions (P = .006) for the G-CSF primed. Multivariate analysis of prognostic factors identified CD34+ cell dose as the only additional factor predicting engraftment. Sixty-nine patients are alive at a median follow-up of 15.9 months (range, 7.4 to 63.7). The cumulative probability of 2-year disease-free survival is 59% (95% confidence interval [CI], 36% to 79%) and 39% (95% CI 25% to 55%) for patients with Hodgkin's disease and non-Hodgkin's lymphoma, respectively. CONCLUSION: The use of G-CSF-mobilized PBSC after high-dose myeloablative therapy resulted in a rapid, complete, and sustained hematopoietic recovery. Disease-free survival over 2 years can be achieved in some patients with relapsed lymphoma after high-dose therapy and PBSC transplantation. However, longer follow-up is required to confirm the curability of this approach.

Bone marrow transplantation for myelodysplastic and myeloproliferative syndromes.

Twenty patients (age range, 4 to 48 years; median age, 36 years) with de novo or drug-induced myelodysplastic syndromes or myeloproliferative disorders were treated with myeloablative immunosuppressive therapy followed by bone marrow transplantation (BMT). Four preparative regimens were used; three regimens consisted of combined total body irradiation (TBI) and chemotherapy and one of combination chemotherapy only. One patient received marrow from his identical twin brother, whereas the other 19 patients were grafted with marrow from histocompatible siblings. In 19 patients the abnormal clone was at least temporarily ablated, while in one patient the congenital myelodysplasia persisted. Eight patients are alive and well for +108 to +3,359 days post-transplantation. Nine patients died of transplant-related complications (six of interstitial pneumonia, two of gastrointestinal bleeding, and one of fungal sepsis) and three patients died with persisting or recurring disease. One patient with a late recurrence has undergone a second successful bone marrow transplant procedure. Outcome of BMT was not related to French-American-British (FAB) type, marrow fibrosis, cytogenetic abnormalities, or preparation regimen. Marrow transplantation as a means of providing long-term disease-free survival and possible cure should be considered in patients if a suitable donor is available.

Solid cancers after bone marrow transplantation.

PURPOSE: To evaluate the incidence and associated risk factors of solid cancers after bone marrow transplantation (BMT). PATIENTS AND METHODS: We analyzed 2,129 patients who had undergone BMT for hematologic malignancies at the City of Hope National Medical Center between 1976 and 1998. A retrospective cohort and nested case-control study design were used to evaluate the role of pretransplantation therapeutic exposures and transplant conditioning regimens. RESULTS: Twenty-nine patients developed solid cancers after BMT, which represents a two-fold increase in risk compared with a comparable normal population. The estimated cumulative probability (+/- SE) for development of a solid cancer was 6.1% +/- 1.6% at 10 years. The risk was significantly elevated for liver cancer (standardized incidence ratio [SIR], 27.7; 95% confidence interval [CI], 1.9 to 57.3), cancer of the oral cavity (SIR, 17.4; 95% CI, 6.3 to 34.1), and cervical cancer (SIR, 13.3; 95% CI, 3.5 to 29.6). Each of the two patients with liver cancer had a history of chronic hepatitis C infection. All six patients with squamous cell carcinoma of the skin had chronic graft-versus-host disease. The risk was significantly higher for survivors who were younger than 34 years of age at time of BMT (SIR, 5.3; 95% CI, 2.7 to 8.6). Cancers of the thyroid gland, liver, and oral cavity occurred primarily among patients who received total-body irradiation. CONCLUSION: The risk of radiation-associated solid tumor development after BMT is likely to increase with longer follow-up. This underscores the importance of close monitoring of patients who undergo BMT.

In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission.

PURPOSE: To evaluate in a prospective study the efficacy of autologous bone marrow transplantation (BMT) in adult patients with acute myelogenous leukemia (AML) in first remission, using a single course of high-dose Cytarabine (HD Ara-C) consolidation therapy as in vivo purging. PATIENTS AND METHODS: Sixty consecutive adult patients with AML in first complete remission (CR) were treated with HD Ara-C consolidation therapy as a method of in vivo purging before marrow collection. High-dose therapy consisted of fractionated total-body irradiation (FTBI) 12 Gy, intravenous etoposide 60 mg/kg, and cyclophosphamide 75 mg/kg, followed by reinfusion of cryopreserved marrow. RESULTS: Sixty patients underwent consolidation treatment with HD Ara-C with the intent to treat with autologous BMT. Sixteen patients were unable to proceed to autologous BMT (10 patients relapsed, one died of sepsis, one developed cerebellar toxicity, two had inadequate blood counts, and two refused). Forty-four patients underwent autologous BMT and have a median follow-up time of 37 months (range, 14.7 to 68.7) for patients who are alive with no relapse. The cumulative probability of disease-free survival (DFS) at 24 months in the intent-to-treat group is 49% (95% confidence interval [CI], 37% to 62%) and in those who actually underwent autologous BMT is 61% (95% CI, 46% to 74%). The probability of relapse was 44% (95% CI, 31% to 58%) and 33% (95% CI, 20% to 49%) for the intent-to-treat and autologous BMT patients, respectively. CONCLUSION: This approach offers a relatively high DFS rate to adult patients with AML in first CR. The results of this study are similar to those achieved with allogeneic BMT.

High frequency of pro-B acute lymphoblastic leukemia in adults with secondary leukemia with 11q23 abnormalities.

To evaluate the frequency and cytogenetic and immunophenotypic features of therapy-related, precursor B-cell acute lymphoblastic leukemia (ALL), 152 cases of immature B-cell ALL were reviewed. These were compared to the frequency of therapy-related acute myeloid leukemia (t-AML) during the same time period. Eight ALL cases with a prior diagnosis of malignancy were identified, including six (4.0%) with prior therapy considered to be therapy-related ALL (t-ALL). The t-ALL cases followed treatment for breast carcinoma (two cases), lung carcinoma (two cases), lymphocyte predominance Hodgkin's disease and follicular lymphoma with a latency period of 13 months to 8 years. All t-ALL cases had a pro-B (CD10-negative) immunophenotype with significantly higher expression of CD15 and CD65, compared to the de novo CD10-positive ALL cases. All six t-ALL cases had MLL abnormalities by fluorescence in situ hybridization, and four showed t(4;11)(q21;q23). These represented half of all 11q23-positive adult ALL cases. During the same time period, 4.9% of all AML cases were considered t-AML. There was a 16.7% frequency of 11q23 abnormalities in the t-AML group. Despite the similar frequency in therapy-related disease among ALL and AML cases, there were differences in the frequency of the diseases and t-ALL represented 12% of all therapy-related leukemias. However, t-ALL represented 46% of all 11q23-positive therapy-related leukemias. The immunogenetic features of t-ALL appear distinct and may aid in identifying more cases of this disease type in the future.

Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission.

Between 1984 and 1997, 23 consecutive patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in first complete remission were treated with allogeneic bone marrow transplants from HLA-matched siblings. All patients but one were conditioned with fractionated total body irradiation (1320 cGy) and high-dose etoposide (60 mg/kg). One patient received high-dose cyclophosphamide instead of etoposide, and another patient received both drugs. Nine patients died following BMT, two from relapsed leukemia, and seven from transplant-related causes. The 3-year probabilities of disease-free survival and relapse are 65% and 12%, respectively. For patients transplanted after 1992, these probabilities are 81% (48-95%, 95% confidence interval) and 11% (2-50%), respectively. The relatively low relapse rate in this group of patients compared to published reports may reflect the enhanced anti-leukemic activity of etoposide in combination with FTBI compared to other conditioning regimens. The enhancement in overall survival for patients transplanted after 1992 may reflect improvements in supportive care, in particular, the prophylaxis of serious fungal and viral infections.

High-dose cytosine arabinoside and daunorubicin induction therapy for adult patients with de novo non M3 acute myelogenous leukemia: impact of cytogenetics on achieving a complete remission.

Cytogenetic abnormalities are used to define prognostic subgroups of acute myelogenous leukemia (AML) with respect to achieving complete remission (CR) and remaining disease free. These prognostic groups for obtaining CR were based on an induction regimen mainly using standard dose cytosine arabinoside (Ara-C) + daunorubicin (DNR). We have reviewed our experience with 122 adult patients with de novo non-M3 AML who were treated with high-dose (HD) Ara-C 3 g/m2 given over 3 h every 12 h for a total of eight doses followed by DNR 60 mg/m2 daily for 2 days. CR was obtained in 80% while 16% had refractory disease and 4% died of sepsis during hypoplasia. CR rate for favorable, intermediate and unfavorable cytogenetic groups were 87%, 79% and 62%, respectively (P = 0.32). High white blood cell count, age, FAB subtype and LDH levels did not adversely affect CR rate. Eighty-five percent of patients achieved CR with one course of treatment and 87% of complete responders were able to receive post remission therapy. High-dose Ara-C/DNR appears to offer an excellent chance of achieving remission for patients with AML including those with poor risk cytogenetics, without an increase in early toxic deaths.

Antiproliferative effects of lipoxygenase inhibitors on malignant human hematopoietic cell lines.

Eicosanoids regulate a wide spectrum of cellular processes including cell proliferation. We have shown previously that lipoxygenase metabolites of arachidonic acid modulate normal human hematopoiesis by in vitro colony assays. In this study we investigated the role of lipoxygenase metabolites in regulating the proliferation of several malignant hematopoietic cell lines, including K562 and EM-2 (chronic myelogenous leukemia blasts), HL-60 (promyelocytic leukemia cells), and U937 (malignant histiocytes). Piriprost, a specific inhibitor of 5-lipoxygenase, inhibits proliferation of these cell lines up to 95% with 50% cell inhibition at approximately 3 x 10(-5) M. Other less specific lipoxygenase inhibitors such as caffeic acid, nordihydroguaiaretic acid, and BW755C have similar activity in a [3H]-thymidine incorporation assay. In contrast, indomethacin, which is a cyclooxygenase inhibitor, has no suppressive effect in these assays. Inhibition by these drugs is completely reversible. Several nonhematopoietic malignant cell lines do not appear to be affected by these drugs. Two specific lipoxygenase metabolites, leukotriene B4 and leukotriene D4, stimulate leukemia cell line proliferation to 150% of control levels when added directly to cell cultures. These data suggest that certain lipoxygenase products, perhaps leukotrienes, are critical for the proliferation of malignant hematopoietic cells in vitro.

Inhibition of bcr-abl oncogene expression by novel deoxyribozymes (DNAzymes).

Deoxyribozymes, or DNA enzymes (DNAzymes), are novel nucleic acids that have the ability to bind to specific sequences of RNA, and to cleave the target site catalytically. DNAzymes are smaller and more efficient enzymatically than ribozymes (RZs), which are catalytic nucleic acids synthesized from ribonucleotides. We have designed three DNAzymes that specifically target the two variants of the p210 bcr-abl gene (splice 1, b3a2; splice 2, b2a2) and the p190 variant (ela2). The cleavage sites for these DNAzymes are located 5 nucleotides (nt) 5' from the fusion site for b3a2, and only 1 nt 5' from the fusion sites for b2a2 and e1a2. We have shown in cell-free in vitro cleavage assays that these DNAzymes efficiently cleave their respective substrates. Mutated DNAzymes, in which only one critical base has been altered, do not cleave these targets. We have used a serum-resistant cytofectin (GS 2888; Gilead) to transfect the DNAzymes into target K562 cells, which express p210bcr-abl. In short-term transfection assays, the DNAzymes specifically inhibited p210bcr-abl protein expression by K562 cells by about 40%, and inhibited cell growth by more than 50% in a 6-day liquid culture assay. We have also transfected freshly isolated CD34+ bone marrow cells from patients with CML with the DNAzymes, which specifically inhibited the growth of bcr-abl-positive CFU-Mix colonies by 53-80%. The potential advantages of anti-bcr-abl DNAzymes over RZs include the following: DNAzymes are much less expensive to synthesize; they are more resistant to serum; and the anti-b2a2 DNAzyme cleaves at a site only 1 nt away from the fusion site, whereas its hammerhead RZ counterpart cleaves this target at a site 8 nt 3' to the fusion site, well within abl exon 2. DNAzymes are novel RNA-cleaving molecules that may significantly improve our ability to inhibit bcr-abl oncogene expression in Ph-positive target cells.

Cutaneous effects of topical indomethacin, an inhibitor of prostaglandin synthesis, on UV-damaged skin.

Topical application of a 2.5 per cent indomethacin (IM) solution to the sunburned skin of humans and guinea pigs resulted in a marked decrease in ultraviolet light (UVL) -induced erythema. In humans, a decrease in skin temperatute and hyperalgesia to near normal levels was also observed. Epidermal responses to UVL injury such as keratinocyte cell death and altered DNA synthesis proceeded unmodified by IM. Repeated applications of IM in the 48-hr period following UVL exposure did not improve upon the results obtained following a single treatment. Guinea-pig skin provides a relevant model system for evaluating the effects of topical nosteroidal anti-inflammatory agents on sunburn.

Radiographic measurement of topical corticosteroid-induced atrophy.

Soft tissue x-ray techniques were used to measure skin thickness as influenced by the chronic usage of topical corticosteroids. In a double-blind study commercial preparations of 1% hydrocortisone (HC), 0.1% triamcinolone acetonide (TA), and a placebo cream were compared for their ability to produce atrophy in normal human forearm skin. After 8 weeks of topical application of the creams, only TA produced clinically apparent atrophy. The average percent decreases in skin thickness measured after 8 weeks of treatment with placebo, HC, or TA were 6.0%, 6.0%, and 17.1%, respectively. During the first week after cessation of treatment the clinical appearance of the skin began to improve and by 1 month all treated skin areas had essentially returned to pretreatment thickness.

Polymyositis as a manifestation of chronic graft-versus-host disease.

A syndrome indistinguishable from idiopathic polymyositis occurred in 11 patients as a manifestation of chronic GVHD. All patients had elevation of creatine phosphokinase (CPK). Immunohistology demonstrated the effector cells in the muscle infiltrates as cytotoxic T cells, a finding similar to idiopathic polymyositis. Polymyositis is a rarely reported complication of chronic graft-versus-host disease (GVHD) with only 8 cases described in the literature. We encountered this syndrome in a small but significant percentage of our patients with chronic GVHD. Polymyositis associated with chronic GVHD does not affect the overall prognosis for the patient. Moreover, polymyositis can be the only manifestation of chronic GVHD. Awareness of this complication is important because it can be confused with other causes of muscle weakness after bone marrow transplantation. Finally, prompt initiation of corticosteroid therapy results in a rapid improvement of the associated symptoms.

Staining of cellular mitochondria with LDS-751.

We have found the dye LDS-751 to bind almost exclusively to mitochondria when incubated with viable, nucleated cells. Treatment of cells with the nuclear stain acridine orange and LDS-751 revealed little colocalization when the cells were examined by confocal microscopy. Staining with the dye rhodamine 123, which is known to bind polarized mitochondria, was virtually identical to the pattern observed with LDS-751. This staining pattern was observed to be consistent over a range of 0.02-20 microg/ml LDS-751 and was consistent between both fibroblasts and monocytes. Depolarization of mitochondria with the mitochondrial depolarizing agents phenyl arsine oxide and carbonyl cyanide m-chlorophenylhydrazone (CCCP) dramatically reduced both LDS-751 staining, and rhodamine 123 fluorescence. Taken together, these results suggest that LDS-751 is excluded from the nucleus and binds the polarized membranes of mitochondria. Given this, interpretation of LDS-751 fluorescence as being indicative of nuclear status, as is commonly done to discriminate between leukocytes and erythrocytes, is unwarranted and may lead to erroneous conclusions if mitochondria become depolarized upon processing.

Inhibition of human monocyte antigen presentation, but not HLA-DR expression, by cyclosporine.

The effects of cyclosporine (CsA) on antigen-dependent human T cell proliferation have been studied using tetanus toxoid as the antigen. CsA significantly inhibited antigen-dependent T cell proliferation at concentrations as low as 0.1 microgram/ml. In dissecting this system we found that preexposure of separated monocytes to CsA during the period of antigen processing led to a marked inhibition of proliferation of T cells added subsequently to the monocytes. We investigated whether this suppressive effect on monocyte antigen presentation was related to monocyte HLA-DR expression, interleukin 1 (IL-1) production, or prostaglandin (PG) secretion. None of these functions seemed to be affected by CsA. In particular, human monocyte HLA-DR expression was not inhibited by CsA, even at concentration of 10 micrograms/ml. The addition of exogenous IL-1 or indomethacin did not reverse the inhibitory effects of CsA. These experiments demonstrate that CsA inhibits antigen-dependent human T cell proliferation, at least in part by acting directly on human monocytes to inhibit antigen presentation. The mechanism of action seems to be independent of IL-1 production, PG secretion, and HLA-DR expression.

Persistence of bcr-able gene expression following bone marrow transplantation for chronic myelogenous leukemia in chronic phase.

The bcr-abl RNA transcript is the molecular counterpart of the Philadelphia chromosome and is detectable by an extremely sensitive polymerase chain reaction assay in most patients with chronic myelogenous leukemia. To determine the effectiveness of ablative radiochemotherapy and bone marrow transplantation in eradicating molecular evidence of the malignant clone, we assayed for bcr-abl RNA expression in specimens from 19 patients with CML in chronic phase (CP) who have survived for at least one year post-BMT. We correlated these results with the patients' remission status based on cytogenetic analysis and BM morphology, and with evidence of mixed hematopoietic chimerism by analysis of RBC antigen and DNA restriction fragment length polymorphism patterns. Thirteen of the 19 patients had detectable bcr-abl RNA at some time following BMT. Twelve of these patients have remained in remission by morphologic and karyotypic criteria from 16.6 to 63.7 months following BMT. One of these 13 patients relapsed both by cytogenetic and clinical criteria at 28.1 months after BMT. Six of these 13 patients are still positive at the time of their most recent analysis. Only two patients have evidence for mixed chimerism of normal hematopoietic elements by either RBC antigen or DNA RFLP patterns. These results suggest that, in some patients transplanted for CML in CP, small numbers of residual leukemic cells may persist or reappear transiently without leading to clinical relapse. The definition of complete remission in CML may need to be revised in light of the enhanced ability to detect minimal residual disease by PCR technology.

Bone marrow transplantation for acute nonlymphoblastic leukemia during first complete remission. An analysis of prognostic factors.

Sixty-nine patients with acute nonlymphocytic leukemia in first remission received total-body irradiation and chemotherapy followed by allogeneic bone marrow transplantation from histocompatible sibling donors. Patient age was between 1 and 41 years: 20 patients 1-19 years (group 1); 27 patients 20-29 years (group 2); and 22 patients 30-41 years (group 3). Two pretransplant radiochemotherapy regimens were employed: The first 45 patients received total-body irradiation (in a single dose) with cytosine arabinoside and cyclophosphamide; the next 24 patients received total-body irradiation (in a fractionated schedule) with cyclophosphamide alone. For all patients, actuarial disease-free survival is 51% (37 of 69 patients are alive and in continuous remission between 5 months and 9.3 years, median 3.7 years). For group 1 actuarial survival is 56%, group 2 48%, and group 3 48%. When analyzed for pretransplant factors that might predict disease-free survival after bone marrow transplantation neither patient age, white cell count at the time of diagnosis, FAB leukemic subtype, length of time before achieving remission, nor length of time between remission and bone marrow transplantation were established as prognostic.

Allogeneic bone marrow transplantation for acute lymphoblastic leukemia during first complete remission.

Patients with acute lymphoblastic leukemia who have poor prognostic features at diagnosis usually have a short disease-free survival in spite of successful remission induction. Those poor risk features are: age over 30 years, a white blood cell count over 25,000/microliter, certain translocations of chromosomes, and requirement for more than six weeks of induction chemotherapy to attain a complete remission. We have used high-dose radiochemotherapy to prepare 39 patients with acute lymphoblastic leukemia in first complete remission (1 infant and 38 adults; median age 23 years) for bone marrow transplantation from histocompatible sibling donors. Thirty-one of the 39 patients in this study had one (n = 23) or more (n = 8) poor risk features: age (n = 7); high white blood cell count (n = 19); translocations (n = 4), or resistance to initial induction therapy (n = 11). Currently, 26 patients are surviving for 4-72 months (median 18 months) following marrow grafting and are in complete remission. One of the surviving patients had two marrow transplant procedures because of recurrent leukemia. Actuarial survival in complete remission is 63% for the entire group of 39 patients and is 60% if the eight patients who had no poor risk features are excluded from analysis. The following causes for failure were observed: leukemic relapse was encountered in four patients between 3 and 17 months after BMT for an actuarial relapse rate of 16%; bacterial sepsis was the cause of death in two patients; graft-versus-host disease and/or interstitial pneumonia led to the demise of seven patients, and one patient died with leukoencephalopathy. It appears that high-dose radiochemotherapy followed by bone marrow transplantation from a histocompatible sibling donor during first complete remission can result in a high disease-free survival rate for younger adults with poor-risk acute lymphoblastic leukemia. This concept needs to be tested in prospective trials comparing bone marrow transplantation with chemotherapy.