A random walk rule for phase I clinical trials.

We describe a family of random walk rules for the sequential allocation of dose levels to patients in a dose-response study, or phase I clinical trial. Patients are sequentially assigned the next higher, same, or next lower dose level according to some probability distribution, which may be determined by ethical considerations as well as the patient's response. It is shown that one can choose these probabilities in order to center dose level assignments unimodally around any target quantile of interest. Estimation of the quantile is discussed; the maximum likelihood estimator and its variance are derived under a two-parameter logistic distribution, and the maximum likelihood estimator is compared with other nonparametric estimators. Random walk rules have clear advantages: they are simple to implement, and finite and asymptotic distribution theory is completely worked out. For a specific random walk rule, we compute finite and asymptotic properties and give examples of its use in planning studies. Having the finite distribution theory available and tractable obviates the need for elaborate simulation studies to analyze the properties of the design. The small sample properties of our rule, as determined by exact theory, compare favorably to those of the continual reassessment method, determined by simulation.

Oral and pharyngeal herpes simplex virus infection after allogeneic bone marrow transplantation: analysis of factors associated with infection.

This study analyzed factors associated with acute oropharyngeal herpes simplex virus (HSV) infection in 627 patients who had undergone allogeneic bone marrow transplantation for leukemia, lymphoma, or aplastic anemia. HSV infection developed in 233 (37%) of the patients; all but two were seropositive for HSV before transplant. Sixty-two percent of the seropositive patients had at least one episode of HSV reactivation during the first 100 days after transplant. Other factors that placed patients at increased risk for HSV infection were a pretransplant diagnosis of leukemia, being in remission at the time of transplant, and/or having been conditioned for transplant with chemoradiotherapy. Recognition of factors that may predispose patients to HSV infection helps determine those transplant recipients who might benefit most from antiviral prophylaxis or other approaches to prevention of HSV reactivation.

Simultaneous infusion of high-dose cytosine arabinoside with cyclophosphamide followed by total body irradiation and marrow infusion for the treatment of patients with advanced hematological malignancy.

Nine patients with advanced hematological malignancy were entered into a phase I study to determine the maximum tolerated doses of cytosine arabinoside (Ara-C) and cyclophosphamide (CY) combined with a standard dose of total body irradiation (TBI). Ara-C was administered continuously over 36 h and two doses of CY were given at 24-h intervals during Ara-C administration. TBI was given as 2.0 Gy fractions on each of 6 consecutive days followed by bone marrow transplantation. The initial three patients received a total dose of 6048 mg/m2 of Ara-C and 84 mg/kg of CY, with two of three patients experiencing fatal toxicity. The next two patients received a total dose of 5040 mg/m2 of Ara-C and 70 mg/kg of CY and both experienced fatal toxicity. The next four patients received a total dose of 3024 mg/m2 of Ara-C, 56 mg/kg of CY; two patients had no toxicity but two had grade 4 (fatal) toxicity. Four of the six patients with fatal toxicity did not complete the TBI regimen and two of these did not receive marrow infusion. One patient is alive (greater than 547 days post-transplant) but has relapsed (day 305). It is concluded that phase I trials of regimens containing concurrent administration of Ara-C and CY may not be appropriate due to severe dose-independent toxicity as demonstrated in this study.

Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation.

We conducted a randomized, double-blind comparison of prednisone and placebo (group I) v prednisone and azathioprine (1.5 mg/kg/day) (group II) as early treatment of extensive chronic graft-v-host disease (GVHD). Patients with platelet counts less than 100,000/microL were placed into therapy with prednisone alone (group III). All three groups received identical doses of prednisone (1 mg/kg every other day) and one double-strength trimethoprim-sulfamethoxazole (TMP-SMX) tablet twice daily. Between January 1980 and December 1983, 179 previously untreated patients were enrolled and 164 were evaluable. Patients randomized to group I (n = 63) and group II (n = 63) were well matched for prognostic factors; those placed into group III (n = 38) had more frequent acute GVHD and progressive onset of chronic GVHD. Median duration of therapy was 2 years. Complications included diabetes (5%), aseptic necrosis (5%) and infection. For groups I, II, and III, the respective incidence of infection was disseminated varicella, 11%, 24%, 34%; bacteremia, 6%, 11%, 34%; and interstitial pneumonia, 5%, 14%, 18%. Recurrent malignancy was the most frequent cause of death and did not differ significantly across the groups. Nonrelapse mortality, however, did differ: 21% in group I, 40% in group II, and 58% in group III (I v II, P = .003; I v III, P = .001). Forty patients in group I, 30 in group II, and 10 in group III survive with a minimum follow-up of 3.8 years. Karnofsky performance scores for 68 survivors are 90% to 100%, scores for seven survivors are 70% to 89% and scores for five survivors are less than 70%. Actuarial survival at 5 years after transplant is 61% in group I, 47% in group II, and 26% in group III (I v II, P = .03; I v III, P = .0001). Treatment with prednisone alone results in fewer infections and better survival than prednisone and azathioprine in standard-risk chronic GVHD. Treatment with prednisone alone is less effective in high-risk patients with thrombocytopenia, and other strategies are required.

Early oral changes following bone marrow transplantation.

This study assessed and analyzed the early oral changes following chemoradiotherapy and bone marrow transplantation. The most notable changes involved mucosal color (white and red), atrophy, vascularity, ulceration, increased salivary viscosity and xerostomia, and the patients' subjective complaints of dryness and oral pain. The ventral tongue, buccal and labial mucosa, and marginal gingiva manifested the most notable changes, while the palate was least affected. The overall trend was for the oral changes to begin slightly before transplantation, to worsen over the first 2 weeks after transplantation, and then to resolve progressively over the remainder of the study period. These oral changes appear to result from a number of insults, including the conditioning chemoradiotherapy, posttransplant immunosuppressive chemotherapy, xerostomia, local trauma, oral infections (especially those caused by HSV), and possibly acute GVHD. Oral HSV infection and/or acute GVHD should especially be considered if the oral status markedly worsens 21 days or more after transplant.

Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation.

Patients undergoing allogeneic bone marrow transplantation who are seropositive for cytomegalovirus are vulnerable to serious cytomegalovirus infection, presumably because of reactivation of latent endogenous virus and severe immunosuppression. We administered intravenous acyclovir from 5 days before to 30 days after allogeneic marrow transplantation for hematologic neoplasms in an effort to prevent cytomegalovirus infection and disease in patients seropositive for cytomegalovirus before transplantation. Eighty-six patients seropositive for both cytomegalovirus and herpes simplex virus before transplantation received acyclovir, whereas 65 patients seropositive only for cytomegalovirus served as controls (acyclovir is the standard prophylactic agent against herpes simplex virus in this setting). The probability that cytomegalovirus infection would develop within the first 100 days after transplantation was 0.70 among acyclovir recipients and 0.87 among control patients at medians of 62 and 40 days after transplantation, respectively (P = 0.0001 by log-rank test). Invasive cytomegalovirus disease developed in 19 acyclovir recipients (22 percent) and 25 control patients (38 percent) (P = 0.008). Survival within the first 100 days after transplantation was better among acyclovir recipients (P = 0.002). Acyclovir prophylaxis was associated with a relative risk of 0.5 or less for the development of cytomegalovirus infection or disease or for death within the first 100 days after transplantation (P less than or equal to 0.04), in proportional-hazards regression analysis. We conclude that prophylaxis with intravenous acyclovir significantly reduced the risk of both cytomegalovirus infection and cytomegalovirus disease in seropositive patients after allogeneic bone marrow transplantation and that it was also associated with significantly improved survival.

Prophylactic use of human leukocyte interferon after allogeneic marrow transplantation.

STUDY OBJECTIVE: To determine the efficacy of prophylactic interferon for prevention of cytomegalovirus infection and relapse of leukemia after allogeneic marrow transplantation. DESIGN: Randomized trial with intermittent interferon administration to day 80 after transplantation. SETTING: Marrow transplantation units of a cancer research center. PATIENTS: Consecutive patients with acute lymphocytic leukemia in remission at the time of transplantation. Thirty-nine patients received interferon, and 40 were control patients. INTERVENTIONS: Partially purified human leukocyte interferon given every 3 days beginning after marrow engraftment and continuing to day 80 after transplantation. After initial safety testing, the starting and minimum dose was 6 X 10(4) units/kg of body weight, with dose escalations determined by the circulating neutrophil count. Transplant conditioning and post-transplantation prophylaxis of graft-versus-host disease with methotrexate followed standard procedures. MEASUREMENTS AND MAIN RESULTS: No difference was observed in the probability or severity of cytomegalovirus infection or in the probability or severity of graft-versus-host disease. Relapse of leukemia occurred in 9 interferon recipients and 21 control patients, with a minimum follow-up of 4 years among surviving patients. The probability of relapse among all interferon recipients was 0.36 (95% confidence interval [Cl], 0.56 to 0.17) and among all control patients was 0.74 (95% Cl, 0.91 to 0.58) (p = 0.04 by log-rank test). Among patients who received transplants in first or second remission, the probability of relapse among interferon recipients was 0.19 (95% Cl, 0.37 to 0.02) compared with 0.71 (95% Cl, 0.97 to 0.51) among control patients (p = 0.008 by log-rank test). Survival rates did not differ between interferon recipients and control patients. Transient decreases in leukocyte count and anorexia and nausea occurred among interferon recipients. Six interferon recipients, all of whom had received chemoradiotherapy of the central nervous system before transplantation, developed leukoencephalopathy after transplantation. CONCLUSIONS: These data suggest that interferon given after transplantation reduces the risk for subsequent relapse of leukemia. The effect of longer administration and of administration in patients with other underlying diseases will require additional trials. No effect was observed on cytomegalovirus infection, either because interferon was not initiated until a median of 18 days after transplantation or because of a lesser effect among marrow allograft recipients.

Risk factors for airflow obstruction in recipients of bone marrow transplants.

Obstructive lung disease is a complication of bone marrow transplantation. To identify risk factors we analyzed pulmonary function tests of 281 adult patients 1 year after marrow transplantation. The forced expiratory volume at 1 second divided by the forced vital capacity (FEV1/FVC) was used to measure airflow rates. Factors associated with a lower year-1 FEV1/FVC (%) included increased age (p less than 0.0001), male gender (p = 0.02), cigarette smoking (p = 0.01), lower FEV1/FVC before transplantation (p less than 0.0001), HLA-nonidentical grafts (p = 0.001), chronic graft-versus-host disease (p = 0.0002), and immunosuppressive therapy with methotrexate (p = 0.01). There was no significant association between the year-1 FEV1/FVC and underlying disease, dose of conditioning irradiation, or development of acute graft-versus-host disease. Linear multivariate regression analysis, after controlling for the FEV1/FVC before transplantation, shows both chronic graft-versus-host disease and administration of methotrexate independently associated with decrements in the year-1 FEV1/FVC. The combined occurrence of chronic graft-versus-host disease and methotrexate also was strongly associated with decreases in the year-1 FEV1/FVC, indicating an interaction of these risk factors.

Sequential intravenous and twice-daily oral acyclovir for extended prophylaxis of herpes simplex virus infection in marrow transplant patients.

To define an effective and convenient means for providing extended prophylaxis of herpes simplex virus (HSV) infection to chronically immunocompromised patients, we studied a two-part regimen of intravenous, followed by oral, acyclovir after marrow transplantation. Seropositive patients were first given intravenous acyclovir until day 30 after transplant. Intravenous acyclovir (250 mgm/m2) given twice daily to 34 patients during this period was 90% virologically effective among those completing the prophylactic course. A randomized, double-blind comparison of twice-daily oral acyclovir (800 mg) and placebo was then conducted from day 31 to day 75 after transplant in 51 patients. Oral acyclovir significantly delayed the median time to first excretion of HSV when compared with placebo (greater than 100 vs. 70 days after transplant, P = 0.0006) and was completely effective in all patients for the duration of drug administration. Patients receiving extended prophylaxis appeared to have less-severe HSV infection when later recurrences did occur. Sequential intravenous and oral acyclovir given twice daily is an effective and convenient regimen for extended prophylaxis of HSV infection following marrow transplantation, and should be useful in other transplant patients or other chronically immunosuppressed patients as well.

Experimental radioimmunotherapy of murine lymphoma with 131I-labeled anti-T-cell antibodies.

We have shown previously that 131I-labeled antibodies against the Thy-1.1 differentiation antigen can cure AKR/Cum (Thy-1.2+) mice bearing AKR/J (Thy-1.1+) SL2 T-cell lymphoma. In the present study we have extended these studies to the therapy of SL2 lymphoma in AKR/J mice, where 131I-anti-labeled Thy-1.1 antibodies react with both tumor and normal T-lymphocytes. A single 25-micrograms bolus of 131I-labeled anti-Thy-1.1 antibody was rapidly cleared from serum by binding to spleen cells (t1/2 less than 3 h) and only low concentrations (less than 2% injected dose/g) were present in tumor 24 h after infusion. Doses of 0.5-5.0 mg antibody saturated cells in the spleen but only slightly increased the proportion of antibody in tumor. In contrast, pretreatment of mice with 1.0 mg of unlabeled anti-Thy-1.1 antibody 24 h prior to 131I-labeled antibody resulted in a tumor concentration of 9.7% injected dose/g 24 h after infusion of the radiolabeled antibody. With this latter regimen, biodistribution approximated that seen in AKR/Cum mice, and infusion of 1,000 mu Ci would result in delivery of 16 Gy to tumor. Therapy of AKR/J mice bearing established s.c. lymphoma nodules with 1,500 mu Ci of 131I-anti-Thy-1.1 antibody given in this latter regimen resulted in complete regression of the nodule in 70% of animals and had a greater antitumor effect (27% complete regression, P less than 0.001) than 750 mu Ci of 131I-labeled irrelevant antibody, a dose that would deliver equivalent radiation to normal organs (liver, kidney, and lung). The anti-Thy-1.1 antibody had only a slightly greater antitumor effect than an equivalent mu Ci dose (1,500 mu Ci) of 131I-labeled control antibody (42% complete regression, P = 0.12). Both antibodies were marrow toxic and all animals treated with 1,500 mu Ci died of marrow aplasia. These studies suggest that radiolabeled antibodies against differentiation antigens may be useful for therapy in spite of binding to normal cell populations but curative therapy may require infusion of unirradiated bone marrow.

Cytomegalovirus immune globulin and seronegative blood products to prevent primary cytomegalovirus infection after marrow transplantation.

In an attempt to prevent primary cytomegalovirus infection after marrow transplantation, we randomly assigned 97 patients who were seronegative for antibody to cytomegalovirus before transplantation to receive one of the following: (1) both intravenous cytomegalovirus immune globulin and seronegative blood products (23 patients); (2) seronegative blood products alone (28 patients); (3) globulin alone (22 patients); or (4) neither treatment (24 patients). Patients not assigned to receive seronegative blood products received unscreened blood products from random donors. The incidence of cytomegalovirus infection according to study group among patients in the study for at least 62 days was 5 percent, 13 percent, 24 percent, and 40 percent, respectively. Among 57 patients with seronegative marrow donors, those who received seronegative blood products had significantly less infection (1 of 32) than those who received standard blood products (8 of 25, P less than 0.007). In contrast, the use of seronegative blood products did not appear to prevent cytomegalovirus infection among patients with seropositive marrow donors. The possibility that cytomegalovirus immune globulin as used in this study can prevent cytomegalovirus infection or ameliorate cytomegalovirus disease was not confirmed, and it cannot be recommended for routine use without additional study.

Risk factors for cytomegalovirus infection after human marrow transplantation.

The records of 545 patients were reviewed for risk factors associated with cytomegalovirus (CMV) infection after marrow transplant. CMV infection occurred among 36% of seronegative patients and 69% of seropositive patients. Among seronegative patients, significant risk factors for CMV infection included positive serology of the marrow donor (relative rate, 2.3) and the use of granulocyte transfusions from seropositive donors (relative rate, 2.5). Among both seronegative and seropositive patients, the occurrence of acute graft-versus-host disease (GVHD) significantly increased the risk of CMV infection (average relative rate, 1.8) and of subsequent CMV pneumonia (average relative rate, 2.6). CMV excretion and viremia were each associated with subsequent pneumonia, but the positive predictive values were low. One-third of long-term survivors excreted CMV at greater than 250 days after transplantation. The only risk factor for late excretion was CMV infection that occurred in the first 150 days after transplantation. In contrast to the effect of acute GVHD on CMV infection, CMV infection did not increase the risk of either acute or chronic GVHD.

Recurrence of acute leukemia more than two years after allogeneic marrow grafting.

The records of 232 patients with acute leukemia in continuous complete remission at two years after a marrow graft from genotypically or phenotypically HLA-identical family member were reviewed. With a followup time of 2-14.2 years, 17 patients have developed recurrent leukemia 2.0-6.3 years after grafting. No relapses have occurred beyond 6.3 years. Actuarial analysis shows a low but significant risk of recurrence of leukemia more than two years after grafting. These data suggest that the majority of the disease-free patients have had their original leukemic clone eliminated. It is important to study the leukemic cells in patients who suffer a relapse more than two years after grafting to determine whether the leukemia is of host or donor origin.

Early and late interstitial pneumonia following human bone marrow transplantation.

Interstitial pneumonia is a major determinant of early and late morbidity and mortality following bone marrow transplantation. Among 952 patients receiving allogeneic marrow grafts in Seattle, 35% developed interstitial pneumonia within 100 days of transplant. Development of early cytomegalovirus (CMV) or idiopathic interstitial pneumonia was infrequent in patients with aplastic anemia prepared only with cyclophosphamide. Use of total body irradiation (TBI) in the transplant preparation, increasing patient age, pretransplant seropositivity for CMV antibody and post-transplant development of graft-versus-host disease (GVHD) all increased the risk of CMV pneumonia. Late interstitial pneumonia was studied in patients with chronic GVHD. Among 198 patients with extensive chronic GVHD, 31 episodes of interstitial pneumonia (seven idiopathic, six CMV, six pneumocystis, five miscellaneous and four unknown causes, and three varicella-zoster) were observed 3-24 months after transplant. In untreated patients with chronic GVHD, 15% developed late interstitial pneumonia. Patients with chronic GVHD who received prednisone +/- azathioprine as immunosuppressive therapy and trimethoprim sulfamethoxazole for infection prophylaxis had an 8% incidence of interstitial pneumonia. Patients with chronic GVHD given immunosuppressive treatment without trimethoprim sulfamethoxazole prophylaxis had a 28% incidence of interstitial pneumonia. Trimethoprim sulfamethoxazole significantly reduced the incidence of late interstitial pneumonia in patients with chronic GVHD (p = 0.001).

The risks of central nervous system relapse and leukoencephalopathy in patients receiving marrow transplants for acute leukemia.

The records of 415 patients who received allogeneic marrow transplants for acute leukemia were reviewed to assess the risk of central nervous system (CNS) relapse and leukoencephalopathy after marrow transplantation. The Kaplan-Meier estimates of the probability of CNS relapse posttransplant were 13% for patients with acute lymphoblastic leukemia (ALL) and 2% for patients with acute nonlymphoblastic leukemia (ANL). Previous CNS disease was significantly correlated with an increased risk of CNS relapse in patients transplanted for ALL but not for ANL. In contrast, bone marrow involvement with leukemia at the time of transplant was associated with an increased risk of CNS relapse in patients with ANL but not in patients with ALL. Seventy-one patients with ALL did not receive posttransplant intrathecal methotrexate (IT-MTX) and 127 did. The probability of CNS relapse in these two groups was 38% and 7%, respectively (P less than .02). This protective benefit from IT-MTX was present in patients both with and without a history of CNS involvement or marrow involvement at the time of transplant. In patients with ANL, 116 patients did not receive posttransplant IT-MTX and 101 patients did, but no protection from CNS relapse was observed from IT-MTX irrespective of a patient's previous CNS history or marrow status at the time of transplant. Leukoencephalopathy was seen exclusively in patients who had received radiation and/or intrathecal chemotherapy to the CNS before preparation for marrow transplantation and posttransplant IT-MTX. In such patients the risk of leukoencephalopathy was 7%. From our data, it appears that posttransplant IT-MTX is a significant benefit for ALL patients in preventing CNS relapse after marrow transplantation. A similar benefit from posttransplant IT-MTX for ANL patients cannot be established from this study. In both groups, increasing total CNS therapy was associated with an increasing risk of leukoencephalopathy.

Infection with varicella-zoster virus after marrow transplantation.

Infection with varicella-zoster virus (VZV) occurred in 231 (16.6%) of 1,394 patients undergoing marrow transplantation in Seattle, Washington, between 1969 and 1982. The probability of VZV infection was 30% by one year after transplant. Eighty percent of infections occurred within the first nine months after transplant, and of these cases 45% had cutaneous or visceral dissemination. Twenty-three deaths were associated with VZV infection, all within the initial nine months after transplant. Postherpetic neuralgia, scarring, and bacterial superinfection were also significantly more frequent among patients with VZV in the first nine months after transplant (32%) than among patients with later infection (19%; P less than .05). By multivariate analysis, allogeneic transplant, acute or chronic graft-vs.-host disease, patient age between 10 and 29 years, diagnosis other than chronic myelogenous leukemia, and posttransplant use of antithymocyte globulin were each risk factors for VZV infection. Among infected patients, the only significant risk factor for VZV dissemination or death was acute graft-vs.-host disease (P less than .03 and P less than .0002, respectively.

Aggressive adriamycin-containing regimen (PM-FAC) in estrogen receptor-negative disseminated breast cancer. Results of a Southwest Oncology Group trial.

Sixty-four patients with disseminated breast cancer were treated with an aggressive chemotherapy program of prednisone, methotrexate, 5-fluorouracil, Adriamycin (doxorubicin) and cyclophosphamide (PM-FAC). A response rate of 76% was seen in 44 estrogen receptor (ER) negative patients, with 26% achieving complete responses. Forty-two percent of 20 ER positive and unknown patients demonstrated a response, but in none was a complete response achieved. Median response duration was 9 months for complete responders and 5 months for partial responders. The median survival for both groups of patients was 13 months. However, survival among the responding patients was inferior for the ER negative group (median, 14 versus 20 months; P = 0.05). These findings suggest selective sensitivity of ER negative breast cancer to Adriamycin-containing chemotherapy. Despite aggressive chemotherapy, no durable remissions were achieved. Relapse occurred at sites of known prior involvement, and in the central nervous system de novo, especially in the ER negative patients.

Marrow transplantation for chronic myelocytic leukemia: a controlled trial of cyclosporine versus methotrexate for prophylaxis of graft-versus-host disease.

Forty-eight patients with chronic myelocytic leukemia, aged 11 to 47, were treated with high-dose cyclophosphamide and fractionated total body irradiation, followed by infusion of marrow from HLA-identical siblings. They were randomized to receive either methotrexate (MTX) (n = 23) or cyclosporine (CSP) (n = 25) as postgrafting prophylaxis for graft-v-host disease (GVHD). All patients had evidence of sustained hematopoietic engraftment. Seventeen of the 25 patients receiving CSP and 17 of the 23 patients receiving MTX are alive between one and almost four (median, 1.7) years, with an actuarial survival rate at three years of 62% and 66%, respectively (P = .60). Also, with respect to most other parameters studied, the two drugs were identical. The probability of acute GVHD was .42 and .46, respectively (P = .70), that of chronic GVHD, .50 and .63 (P = .44), and that of death from transplant-related causes, .30 and .24 (P = .51). There were no differences in the speed of granulocyte and platelet engraftment (P = .82 and .94, respectively), and the duration of hospitalization was comparable (P = .58). Patients receiving MTX required red cell transfusions for a shorter period of time (P = .02), but had a slightly increased morbidity from early oral mucositis. The leukemia recurrence rates were comparable (P = .60). With the regimens used in this study, we conclude that CSP failed to reduce the incidence of GVHD and improve the survival of patients with chronic myelocytic leukemia when compared to results with standard MTX.

Marrow transplantation from related donors other than HLA-identical siblings.

Marrow transplantation has generally been limited to patients with a sibling who is genotypically identical for HLA. In a study of the acceptable limits of HLA incompatibility, 105 consecutive patients with hematologic cancers who received marrow grafts from haploidentical donors (study group) were compared with 728 similar patients concurrently receiving grafts from HLA genotypically identical siblings (control group). The unshared haplotypes differed variably: 12 were phenotypically but not genotypically identical for HLA-A, HLA-B, and HLA-D; 63 differed at one locus (A, B, or D); 24 at two loci; and 6 at three. A higher proportion of study patients had delayed engraftment, granulocytopenia, or graft rejection. Acute graft versus host disease occurred earlier and with greater frequency in study patients. The risk of the disease did not correlate with disparity for Class I (A or B) versus Class II (D-region) loci. Thus, incompatibility for HLA has an important effect on the course after clinical marrow transplantation. In spite of these complications, there was no statistically significant difference in the survival of the study patients and control patients who received their transplants during remission.