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Background: A myeloablative conditioning regimen can be safely given to older patients and those with comorbidities without increasing nonrelapse mortality (NRM) by fractionating the dose of intravenous busulfan. How this approach compares in efficacy with traditional, nonfractionated, lower dose regimens is unknown., Methods: Outcomes were compared in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received either myeloablative, fractionated busulfan (f-Bu) dosed to achieve an area under the curve of 20,000 μmol per minute (f-Bu20K) over 2 weeks (n = 84) or a standard, nonfractionated, lower busulfan dose regimen of 16,000 μmol per minute (Bu16K) over 4 days (n = 78). Both groups also received fludarabine 40 mg/m 2 intravenously for 4 days. Graft-versus-host disease prophylaxis was tacrolimus and methotrexate. Patients in the Bu16K group who had unrelated donors also received antithymocyte globulin. The primary endpoint was progression-free survival., Results: Roughly one-half of the patients were aged >65 years, approximately 40% had poor-risk cytogenetics, approximately 40% of those with AML were not in complete remission, and approximately 40% had a comorbidity index >3. At 2 years, progression-free survival was significantly improved in the f-Bu20K group compared with the Bu16K group (45% vs 24%, respectively; hazard ratio [HR], 0.6; 95% CI, 0.4-0.8; P = .004). This was because of a significant reduction in progression (34% vs 59%, respectively; HR, 0.5; 95% CI, 0.3-0.8; P = .003) without any increase in NRM (21% vs 15%, respectively; HR, 1.4; 95% CI, 0.7-3; P = .3), which resulted in improved overall survival (51% vs 31%, respectively; HR, 0.6; 95% CI, 0.3-0.9; P = .01)., Conclusions: A myeloablative, fractionated busulfan regimen reduces relapse and improves survival without increasing NRM in older patients with AML and myelodysplastic syndrome., (© 2021 American Cancer Society.)

Background: More active high-dose chemotherapy (HDC) regimens are needed for refractory lymphomas. The authors previously combined infusional gemcitabine with busulfan and melphalan (Gem/Bu/Mel) pursuing DNA damage repair inhibition. Subsequently, they combined Gem/Bu/Mel with vorinostat, which facilitates chemotherapy access to DNA. The resulting regimen was safe and synergistic. However, vorinostat induced DNA methyltransferase up-regulation, which could be preclinically abrogated by azacitidine, increasing tumor-cell kill. Those observations led to a clinical combination of azacitidine with vorinostat/Gem/Bu/Mel., Methods: Patients ages 12 to 65 years with refractory or poor-risk relapsed lymphomas were eligible. They received intravenous azacitidine on days -11 through -3 at doses from 15 to 35 mg/m(2) daily (dose levels 1-3), followed by oral vorinostat (1000 mg once daily on days -11 through -3), gemcitabine (2775 mg/m(2) over 4.5 × 2), busulfan (at an area under the receiver operating characteristic curve of 4000 daily × 4), and melphalan (60 mg/m(2) × 2). Patients who had tumors that were positive for CD20 (cluster of differentiation 20; B-lymphocyte antigen) received rituximab on day -9., Results: In total, 60 patients were enrolled, including 26 with diffuse large B-cell lymphoma (DLBCL) (10 double hit/double expressors), 21 with Hodgkin lymphoma, 8 with T-cell lymphoma, and 5 with other B-cell lymphomas. The median patient age was 41 years (range, 16-65 years), patients had received a median of 3 prior lines of chemotherapy (range, 2-7 lines of chemotherapy); and 32% of tumors were positive on positron emission tomography studies at the time of HDC. Two patients died from treatment complications (respiratory syncytial virus pneumonia and sepsis, respectively). The maximum tolerated dose of azacitidine was encountered at dose level 1 (15 mg/m(2) daily). The toxicity profile (mainly mucositis and dermatitis) was manageable and was identical to that of vorinostat/Gem/Bu/Mel. Neutrophils and platelets engrafted promptly. At a median follow-up of 15 months (range, 8-27 months), the event-free and overall survival rates were 65% and 77%, respectively, among patients with DLBCL; 76% and 95%, respectively, among patients with Hodgkin lymphoma; and 88% for both among patients with T-cell lymphoma., Conclusions: Double epigenetic modulation of Gem/Bu/Mel with azacitidine/vorinostat is feasible and highly active in patients with refractory/poor-risk relapsed lymphomas, warranting further evaluation. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2680-2688. © 2016 American Cancer Society., Competing Interests: DISCLOSURES Yago Nieto reports research support from Otsuka Pharmaceuticals, Novartis Pharmaceuticals and Celgene Pharmaceuticals outside the submitted work. Chitra Hosing reports grants for clinical trials from Celgene Pharmaceuticals and personal fees from Sanofi, Aviara Pharmaceuticals, Seattle Genetics, Cardinal Health outside the submitted work. Qaiser Bashir reports research funding from Celgene Pharmaceuticals and Takeda Pharmaceuticals and personal fees from Takeda Pharmaceuticals and Spectrum Pharmaceuticals outside the submitted work. Richard Champlin reports research support from Sanofi and Celgene Pharmaceuticals outside the submitted work. Borje S. Andersson reports personal fees from Otsuka America Pharmaceutical, Inc, outside the submitted work. The remaining authors made no disclosures., (© 2016 American Cancer Society.)

Background: Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) are increasingly likely to have received a novel tyrosine kinase inhibitor (NTKI) after failing imatinib mesylate. It is unknown whether the use of these NTKIs before HSCT increases transplant-related toxicity., Methods: The outcome of 12 patients with CML (1 in chronic phase, 6 in the accelerated phase, and 5 in the blastic phase) who received dasatinib (n = 2), nilotinib (n = 7), or both (n = 3) before HSCT were retrospectively analyzed., Results: The median time on treatment was 134 days, and the median time from the end of NTKI therapy to HSCT was 34 days. The preparative regimen was ablative in 8 patients and nonablative in 4. All patients engrafted within 13 days. There was no significant early transplant-related toxicity. One patient developed secondary graft failure after 6 months from the first HSCT that required a second HSCT. Acute and chronic graft-versus-host disease (GVHD) was observed in 7 and 6 patients, respectively. Nine patients achieved a molecular response: 4 complete and 5 major (quantitative reverse transcriptase-polymerase chain reaction <0.05%). Three patients had disease progression by Day 30 after HSCT. Two patients developed disease recurrence after a median of 12 months. After a median follow-up of 10 months, 7 patients were alive in molecular response and 5 patients had died, 4 of disease progression and 1 of extensive chronic GVHD., Conclusions: Previous treatment with NTKI did not increase transplant-related toxicity in this preliminary experience. Further follow-up and a larger number of patients will be necessary to confirm these observations.

Background: Total body irradiation (TBI) is commonly used with autologous bone marrow transplantation (BMT) for treatment of hematologic malignancies. Pulmonary complications of TBI can cause long-term morbidity and mortality. The authors have compared the pulmonary toxicity and efficacy of two different TBI fractionation regimens in otherwise identical autologous BMT protocols., Methods: Between 1990 and 1997 patients younger than 60 years of age with low-grade lymphoma at high risk of treatment failure were enrolled on one of two sequential protocols for autologous BMT differing only in their TBI regimens. The preoperative chemotherapy regimens were identical and consisted of intravenous etoposide (1500 mg/m(2)) for 1 day, intravenous cyclophosphamide (60 mg/kg) for 2 days, and mesna (10 mg/kg). The TBI used in protocol A consisted of twice-daily fractions of 1.7 grays (Gy) for 3 days to a total of 10.2 Gy through lateral fields, with no lung shielding. In protocol B, the TBI consisted of 3 Gy once daily for 4 days to a total of 12 Gy through anteroposterior fields, with lung shielding (5 half-value layers) during the third dose. Fifty-eight patients were treated on protocol A and 24 on protocol B. The groups were equivalent with regard to age, performance status (PS) and gender. Lung function was assessed objectively by pulmonary function tests (PFTs) before and at intervals after TBI. The pulmonary function parameters assessed included forced vital capacity (FVC), forced expiratory volume in 1 second (FEV(1)), forced expiratory flow between 25% and 75% of vital capacity (FEF(25-75)), diffusing capacity for carbon monoxide (DL(CO)), and total lung capacity (TLC). Each patient's post-TBI PFTs were normalized to the corresponding pre-TBI values and analyzed using a random effects model. Clinical pulmonary function status was scored according to Radiation Therapy Oncology Group criteria for acute and late lung toxicity. All clinical pulmonary toxicities such as pneumonitis, pneumonia, and diffuse alveolar hemorrhage, whether specifically related to TBI or not, were scored. Toxicity was classified as either acute (i.e., occurring within 90 days of TBI) or late (i.e., occurring more than 90 days after TBI). The endpoints of analysis were overall survival (OS), freedom from progression, and chronic pulmonary toxicity. Survival, progression, and complication free survival were computed using the method of Kaplan and Meier., Results: Three-year actuarial OS rates were 66% and 67% for protocols A and B, respectively. Patients 50 years of age or older had a hazard ratio of death 3.5 times higher than younger patients. Freedom from progression was significantly different for the 2 TBI regimens (P < 0.001; log-rank test): 31% at 3 years in the protocol A group compared with 82% in protocol B group. Patients on protocol A had a rate of progression 4.7 times higher than patients on protocol B. The TBI protocols did not differ significantly in their effects on FVC, FEV(1), FEF(25-75), DL(CO), and TLC. Patients 45 years of age or older had lower average posttransplant values of FEV(1), FVC, and DL(CO) than younger patients. There was no significant difference in acute or late toxicity rates between patients on the two protocols. Seven of the 57 patients in the twice-daily TBI (protocol A) group had acute pulmonary events (Grade 3 or greater), compared with 6 of the 24 patients in the once-daily (protocol B) group (P = 0.19). The 3-year freedom from late complications rate was 80% in the protocol A group and 70% in the protocol B group (P = 0.45). Patients with a PS of 1 had a hazard ratio of late complications 3.2 times greater than patients with a PS of 0 (P < 0.001)., Conclusions: It is possible to intensify TBI from a total dose of 10.2 Gy delivered in 6 twice-daily fractions to 12 Gy delivered in 4 once-daily fractions without significantly increasing the risk of pulmonary toxicity. The increased dose may contribute to a decrease in the recurrence rate in these patients. (c) 2001 American Cancer Society.

Background: Indium-111 labeled antiferritin targets 95% of all Hodgkin's disease lesions with a diameter of 1 cm or more. Subsequent treatment with yttrium-90 labeled antiferritin secures a high response rate in patients with recurrent Hodgkin's disease., Methods: A total of 87 patients were entered on one of three different yttrium-90 labeled antiferritin protocols. Recurrences after yttrium-90 treatment were analyzed. Nine patients were retreated with involved external beam radiation fields, selected with the help of indium-111 labeled antiferritin., Results: In single-agent yttrium-90 antiferritin studies, a response rate of more than 60% was found, with an average response duration of 6 months. One-third of the patients had recurrences in previously uninvolved areas. Repeat indium antiferritin scintigraphy allowed for the selection of new radiation fields for recurrences. In-field disease control was obtained for a median of 8 months, but new recurrences in new areas occurred. Chemotherapy or radiation therapy given immediately before antiferritin decreased tumor targeting with indium-111 labeled antiferritin., Conclusions: Recurrences after radiolabeled antiferritin treatment are not due to radioresistant Hodgkin's disease. In contrast, Hodgkin's disease less than 1 cm in diameter is not targeted and not controlled by radiolabeled antiferritin. New multimodality regimens with a higher therapeutic ratio are needed for treatment of Hodgkin's disease with curative intent. Radiolabeled antiferritin can be incorporated in such regimens to secure better control of bulky Hodgkin's disease (>1 cm in diameter), but it should be given before chemotherapy or radiation therapy.

One hundred three relapsed leukemia patients were treated with high-dose cytosine arabinoside (Ara-C); 3 g/m2 intravenously over 2 hours every 6 to 12 hours for a total of nine to 12 doses or 3 g/m2 intravenously over 2 hours for two doses 12 hours apart followed by a continuous infusion of 1.5 g/m2 over 24 hours daily for 3 to 4 days. Thirteen of them developed adult respiratory distress syndrome (ARDS) without having any recognized reason for the development of pulmonary edema. This problem showed no correlation with age or prior chemotherapy. Four of the patients recovered, but in nine this complication was fatal. The authors have reviewed the clinical course of these 13 patients and the postmortem findings of the seven patients who had an autopsy performed. The pulmonary tissue from six patients showed massive edema and one had diffuse alveolar damage. Histologic examination revealed a highly proteinaceous intraalveolar infiltrate without any inflammatory reaction in all cases. Intestinal tissue from all patients revealed changes compatible with cytotoxic damage, and pleura and/or pericardium from six of the seven patients showed an extensive fibrinous exudate suggestive of capillary leakage. The time sequence of the clinical events and the histologic findings indicate that high-dose Ara-C treatment in leukemia may cause a capillary leakage syndrome with ARDS that may progress to fatal respiratory failure.

Systemic aspergillosis is encountered with increasing prevalence in immunocompromised patients undergoing chemotherapy. The current communication describes the clinical and postmortem findings in three leukemic patients who developed myocardial infarction secondary to Aspergillus embolization of the coronary arteries. They were all immunosuppressed owing to previous chemotherapy and had been treated for suspected fungal infection with amphotericin B (0.6 mg/kg) for at least 1 week prior to this episode. It is postulated that the infection was spread through the blood since in all three cases the descending branch of the left coronary artery was occluded. Heart involvement resulting from fungal infection should be suspected when chest symptoms of unknown origin occur in this patient population.

Seventy-four adult patients with acute leukemia in relapse were studied. They received high-dose intravenous boluses of cytosine arabinoside (Ara-C) according to the following schedules: 3 g/m2 over 2 hours, every 12 hours for 4 to 12 consecutive doses, or a continuous infusion over 5 days at 200, 400, or 800 mg/m2/day. The patients' ages ranged from 16 to 68 years (median, 35). Subacute pulmonary failure attributable to Ara-C was observed in 16 of 72 evaluable patients (22%) and appeared 2 to 21 days (median, 6) after the first dose. None of the 28 patients who received up to six doses experienced any toxicity. With repeated courses or more than six doses in the first course there was a sharp increase in the incidence of toxicity. Thus, subacute pulmonary failure developed in 6 of 24 patients who received 9 doses and 6 of 19 patients who received 12 doses. The increase in toxicity with increasing number of doses is significant (P = 0.03). This suggests that the high-dose Ara-C regimen should be used with awareness of possible drug-induced pulmonary toxicity.