Willis H. Navarro

Intensified and Shortened Cyclical Chemotherapy for Adult Acute Lymphoblastic Leukemia

PURPOSE To assess the efficacy and toxicity of a new treatment program of intensified and shortened cyclical chemotherapy (protocol 8707) in adults with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Previously untreated adults < or = 60 years old with ALL were treated with a four-agent induction chemotherapy regimen. This was followed by cyclical postremission therapy with high-dose cytarabine/etoposide; high-dose methotrexate/6-mercaptopurine; and daunorubicin, vincristine, prednisone, and asparaginase. Maintenance chemotherapy with oral methotrexate and 6-mercaptopurine was continued for 30 months. CNS prophylaxis was given with intrathecal methotrexate in addition to the systemic chemotherapy indicated above. RESULTS Seventy-eight of 84 patients (93%) achieved complete remission. With a median follow-up of 5.6 years, 5-year event-free survival (EFS) of all remission patients is 52%. Patients with high-risk features including adverse cytogenetics, failure to achieve remission with the first cycle of chemotherapy, and B-precursor disease with WBC counts more than 100,000/microL all relapsed unless taken off study for transplantation. For patients without these high-risk features, 5-year EFS was 60%. Compared with our previous treatment regimen, results appear to be improved for patients with standard-risk B-precursor disease (5-year EFS, 66% v 34%; P =.01). CONCLUSION Intensified and shortened chemotherapy may improve the outcome for patients with ALL with B-precursor disease lacking high-risk features. Further trials of this regimen are warranted.

Acute toxicities of unrelated bone marrow versus peripheral blood stem cell donation: Results of a prospective trial from the National Marrow Donor Program

Although peripheral blood stem cells (PBSCs) have replaced bone marrow (BM) as the most common unrelated donor progenitor cell product collected, a direct comparison of concurrent PBSC versus BM donation experiences has not been performed. We report a prospective study of 2726 BM and 6768 PBSC donors who underwent collection from 2004 to 2009. Pain and toxicities were assessed at baseline, during G-CSF administration, on the day of collection, within 48 hours of donation, and weekly until full recovery. Peak levels of pain and toxicities did not differ between the 2 donation processes for most donors. Among obese donors, PBSC donors were at increased risk of grade 2 to 4 pain as well as grade 2 to 4 toxicities during the pericollection period. In contrast, BM donors were more likely to experience grade 2 to 4 toxicities at 1 week and pain at 1 week and 1 month after the procedure. BM donors experienced slower recovery, with 3% still not fully recovered at 24 weeks, whereas 100% of PBSC donors had recovered. Other factors associated with toxicity included obesity, increasing age, and female sex. In summary, this study provides extensive detail regarding individualized risk patterns of PBSC versus BM donation toxicity, suggesting donor profiles that can be targeted with interventions to minimize toxicity.

Acute toxicities of unrelated bone marrow versus peripheral blood stem cell donation: results of a prospective trial from the NMDP

Although peripheral blood stem cells (PBSCs) have replaced bone marrow (BM) as the most common unrelated donor progenitor cell product collected, a direct comparison of concurrent PBSC versus BM donation experiences has not been performed. We report a prospective study of 2726 BM and 6768 PBSC donors who underwent collection from 2004 to 2009. Pain and toxicities were assessed at baseline, during G-CSF administration, on the day of collection, within 48 hours of donation, and weekly until full recovery. Peak levels of pain and toxicities did not differ between the 2 donation processes for most donors. Among obese donors, PBSC donors were at increased risk of grade 2 to 4 pain as well as grade 2 to 4 toxicities during the pericollection period. In contrast, BM donors were more likely to experience grade 2 to 4 toxicities at 1 week and pain at 1 week and 1 month after the procedure. BM donors experienced slower recovery, with 3% still not fully recovered at 24 weeks, whereas 100% of PBSC donors had recovered. Other factors associated with toxicity included obesity, increasing age, and female sex. In summary, this study provides extensive detail regarding individualized risk patterns of PBSC versus BM donation toxicity, suggesting donor profiles that can be targeted with interventions to minimize toxicity.

Autologous stem cell transplantation for acute myeloid leukemia in first remission

We studied the feasibility, toxicity, and efficacy of a 2-step approach to autologous stem cell transplantation for patients with acute myeloid leukemia in first remission. Step 1 consisted of consolidation chemotherapy including cytarabine 2000 mg/m2 twice daily for 4 days concurrent with etoposide 40 mg/kg by continuous infusion over 4 days. During the recovery from this chemotherapy, peripheral blood stem cells were collected under granulocyte colony-stimulating factor stimulation. Step 2, autologous stem cell transplantation, involved the preparative regimen of busulfan 16 mg/kg followed by etoposide 60 mg/kg and reinfusion of unpurged peripheral blood stem cells. A total of 128 patients were treated. During step 1, there was 1 treatment-related death. A median CD34+ cell dose of 14 (x10(6)/kg) was collected in 3 aphereses. Ten patients suffered relapse before transplantation, and 117 patients (91%) proceeded to transplantation. During step 2, there were 2 treatment-related deaths, and 35 patients subsequently suffered relapse. With median follow-up of 30 months, 5-year disease-free survival for all patients entered in the study is projected to be 55%. By cytogenetic risk group, 5-year disease-free survival is 73% for favorable-risk patients, 51% for intermediate-risk patients, and 0% for poor-risk patients. We conclude that this 2-step approach to autologous transplantation produces excellent stem cell yields and allows a high percentage of patients to receive the intended therapy. Preliminary efficacy analysis is very encouraging, with outcomes that appear superior to those of conventional chemotherapy.

Lower risk for serious adverse events and no increased risk for cancer after PBSC vs BM donation

We compared serious early and late events experienced by 2726 bone marrow (BM) and 6768 peripheral blood stem cell (PBSC) donors who underwent collection of PBSC or BM between 2004 and 2009 as part of a prospective study through the National Marrow Donor Program. Standardized FDA definitions for serious adverse events (SAEs) were used, and all events were reviewed by an independent physician panel. BM donors had an increased risk for SAEs (2.38% for BM vs 0.56% for PBSC; odds ratio [OR], 4.13; P < .001), and women were twice as likely to experience an SAE (OR for men, 0.50; P = .005). Restricting the analysis to life-threatening, unexpected, or chronic/disabling events, BM donors maintained an increased risk for SAEs (0.99% for BM vs 0.31% for PBSC; OR, 3.20; P < .001). Notably, the incidence of cancer, autoimmune illness, and thrombosis after donation was similar in BM vs PBSC donors. In addition, cancer incidence in PBSC donors was less than that reported in the general population (Surveillance, Epidemiology, and End Results Program database). In conclusion, SAEs after donation are rare but more often occurred in BM donors and women. In addition, there was no evidence of increased risk for cancer, autoimmune illness, and stroke in donors receiving granulocyte colony-stimulating factor during this period of observation.

Obesity Does Not Preclude Safe and Effective Myeloablative Hematopoietic Cell Transplantation (HCT) for Acute Myelogenous Leukemia (AML) in Adults

The incidence of excessive adiposity is increasing worldwide, and is associated with numerous adverse health outcomes. We compared outcomes by body mass index (BMI) for adult patients with acute myelogenous leukemia (AML) who underwent autologous (auto, n = 373), related donor (RD, n = 2041), or unrelated donor (URD, n = 1801) allogeneic myeloablative hematopoietic cell transplantation (HCT) using bone marrow or peripheral blood stem cells reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995 to 2004. Four weight groups by BMI (kg/m(2)) were defined: underweight <18 kg/m(2); normal 18-25 kg/m(2); overweight >25-30 kg/m(2); and obese >30 kg/m(2). Multivariable analysis referenced to the normal weight group showed an increased risk of death for underweight patients in the RD group (relative risk [RR], 1.92; 95% confidence interval [CI], 1.28-2.89; P = .002), but not in the URD group. There were no other differences in outcomes among the other weight groups within the other HCT groups. Overweight and obese patients enjoyed a modest decrease in relapse incidence, although this did not translate into a survival benefit. Small numbers of patients limit the ability to better characterize the adverse outcomes seen in the underweight RD but not the underweight URD allogeneic HCT patients. Obesity alone should not be considered a barrier to HCT.

Second Autologous Stem Cell Transplantation for Relapsed Lymphoma after a Prior Autologous Transplant

We determined treatment-related mortality, progression-free survival (PFS), and overall survival (OS) after a second autologous HCT (HCT2) for patients with lymphoma relapse after a prior HCT (HCT1). Outcomes for patients with either Hodgkin lymphoma (HL, n = 21) or non-Hodgkin lymphoma (NHL, n = 19) receiving HCT2 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) were analyzed. The median age at HCT2 was 38 years (range: 16-61) and 22 (58%) patients had a Karnofsky performance score <90. HCT2 was performed >1 year after HCT1 in 82%. The probability of treatment-related mortality at day 100 was 11% (95% confidence interval [CI], 3%-22%). The 1-, 3-, and 5-year probabilities of PFS were 50% (95% CI, 34%-66%), 36% (95% CI, 21%-52%), and 30% (95% CI, 16%-46%), respectively. Corresponding probabilities of survival were 65% (95% CI, 50%-79%), 36% (95% CI, 22%-52%), and 30% (95% CI, 17%-46%), respectively. At a median follow-up of 72 months (range: 12-124 months) after HCT2, 29 patients (73%) have died, 18 (62%) secondary to relapsed lymphoma. The outcomes of patients with HL and NHL were similar. In summary, this series represents the largest reported group of patients with relapsed lymphomas undergoing SCT2 following failed SCT1, and with long-term follow-up. Our series suggests that SCT2 is feasible in patients relapsing after prior HCT1, with a lower treatment-related mortality than that reported for allogeneic transplant in this setting. HCT2 should be considered for patients with relapsed HL or NHL after HCT1 without alternative allogeneic stem cell transplant options.

Prevalence of conditions associated with human immunodeficiency and hepatits virus infections among persons with haemophilia, 2001-2003

Summary.  Before the mid‐1980s, haemophilia often was unknowingly treated with contaminated plasma products, resulting in high rates of human immunodeficiency virus (HIV‐1), hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To estimate the impact of these infections, a new cohort was established. All HCV‐seropositive patients, age 13–88 years, at 52 comprehensive haemophilia treatment centres were eligible. Cross‐sectional data collected during April 2001 to January 2004 (median June 2002) were analysed. Plasma HIV‐1 and HCV RNA were quantified by polymerase chain reaction. Highly active antiretroviral therapy (HAART) was defined as use of at least three recommended medications. Among 2069 participants, 620 (30%) had HIV‐1. Of 1955 with known HBV status, 814 (42%) had resolved HBV and 90 (4.6%) were HBV carriers. Although 80% of the HIV‐1‐positive participants had ≥200 CD4+ cells μL−1, only 59% were on HAART. HIV‐1 RNA was undetectable in 23% of those not taking antiretroviral medications. Most (72%) participants had received no anti‐HCV therapy. HCV RNA was detected less frequently (59%) among participants treated with standard interferon plus ribavirin (P = 0.0001) and more frequently among HIV‐1‐positive than HIV‐1‐negative participants (85% vs. 70%, P < 0.0001). HIV‐1‐positive participants were more likely to have pancytopenia and subclinical hepatic abnormalities, as well as persistent jaundice, hepatomegaly, splenomegaly and ascites. HAART recipients did not differ from HIV‐negative participants in the prevalence of ascites. The clinical abnormalities were more prevalent with older age but were not confounded by HBV status or self‐reported alcohol consumption. Eleven participants presented with or previously had hepatocellular carcinoma or non‐Hodgkin lymphoma. Although prospective analysis is needed, our data reveal the scale of hepatic and haematological disease that is likely to manifest in the adult haemophilic population during the coming years unless most of them are successfully treated for HIV‐1, HCV or both.

Selection of Adult Unrelated Hematopoietic Stem Cell Donors: Beyond HLA

HLA matching is the dominant controllable donor-recipient factor determining the outcome of adult unrelated donor hematopoietic cell transplantation. Beyond HLA, donor selection is often based on donor characteristics such as age, sex, parity, cytomegalovirus (CMV) serostatus, and ABO blood type. The published evidence to suggest these additional factors are important determinants of survival is weak and is sometimes conflicting. Other factors may be more important for optimal donor selection than the traditional non-HLA factors. These include the donors geographic location, the performance history of the groups managing the donor, a priori knowledge of the donors willingness/availability, and others. Implementation of tools to expose this additional donor-related information could significantly alter and aid unrelated donor selection practices.

Mantle Cell Lymphoma 12 Years After Allogeneic Bone Marrow Transplantation Occurring Simultaneously in Recipient and Donor

A 34-year-old woman was diagnosed with chronic myeloid leukemia in chronic phase in October 1995 after she was found to have an elevated WBC count on routine evaluation. A six of six HLA-matched, sex-mismatched, ABO-mismatched, unrelated donor was identified from the National Marrow Donor Program pool, and in June 1996, the patient underwent a bone marrow transplantation. Her post-transplantation course was complicated by chronic graftversus-host disease. By December 2000, her immunosuppression for graft-versus-host disease was tapered off completely, and her chronic myeloid leukemia remained in morphologic, cytogenetic, and molecular remission. In April 2008, the patient developed cervical and inguinal lymphadenopathy. She underwent a biopsy of a right inguinal lymph node on May 20, 2008, which demonstrated mantle cell lymphoma (MCL) with immunohistochemistry confirming expression of nuclear cyclin D1. She had stage IVA disease with lymphadenopathy, a WBC of 5,200/ L, an absolute lymphocyte count of 900/ L, 5% peripheral blood involvement by flow cytometry, and bone marrow with 1.7% involvement by flow cytometry. Fluorescent in situ hybridization (FISH) analysis of the tumor cells in the lymph node specimen demonstrated that the malignant cells contained the Y chromosome, strongly suggesting that the MCL was donor derived. Figure 1A shows recipient MCL cells at the capsular region, with some of the lymphoma cells infiltrating into the capsules (hematoxylin and eosin H&E, 400). FISH (Fig 1B) highlights the lymphoma cells with XY chromosomes (one orange and one green) in the lymph node and infiltrating the capsule (white arrows), whereas host stroma cells have XX (double green) chromosomes (gold arrows, 1,000). FISH analysis of recipient peripheral blood mononuclear cells for the XY signal revealed 100% donor hematopoietic chimerism at the time of the patient’s MCL diagnosis. This prompted further evaluation of the origin of the MCL. The patient’s stem cell donor is a 61-year-old man who was diagnosed with MCL on May 5, 2008, during the same month as the recipient. He presented with dysphagia and weight loss and was found to have a 3.3-cm tonsillar mass. Biopsy of the mass demonstrated MCL cells (Fig 1C; hematoxylin and eosin, 200). Immunohistochemical staining for cyclin D1 (Fig 1D) demonstrated a homogenous nuclear stain ( 100). Staging studies demonstrated stage IVB disease