Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma.

Background: We previously demonstrated that brentuximab vedotin (BV) used as second-line therapy in patients with Hodgkin lymphoma is a tolerable and effective bridge to autologous hematopoietic cell transplantation (AHCT). Here, we report the post-AHCT outcomes of patients treated with second-line standard/fixed-dose BV and an additional cohort of patients where positron-emission tomography adapted dose-escalation of second-line BV was utilized. Patients and methods: Patients on the dose-escalation cohort received 1.8 mg/kg of BV intravenously every 3 weeks for two cycles. Patients in complete remission (CR) after two cycles received two additional cycles of BV at 1.8 mg/kg, while patients with stable disease or partial response were escalated to 2.4 mg/kg for two cycles. All patients, regardless of treatment cohort, proceeded directly to AHCT or received additional pre-AHCT therapy at the discretion of the treating physician based on remission status after second-line BV. Results: Of the 20 patients enrolled to the BV dose-escalation cohort, 8 patients underwent BV dose-escalation. BV escalation was well-tolerated, but no patients who were escalated converted to CR. Of 56 evaluable patients treated across cohorts, the overall response rate (ORR) to second-line BV was 75% with 43% CR. Twenty-eight (50%) patients proceeded directly to AHCT without post-BV chemotherapy, and a total of 50 patients proceeded to AHCT. Thirteen patients received consolidative post-AHCT therapy with either radiation, BV, or a PD-1 inhibitor. After AHCT, the 2-year progression-free survival (PFS) and overall survival were 67% and 93%, respectively. The 2-year PFS among patients in CR at the time of AHCT (n = 37) was 71% compared with 54% in patients not in CR (p = 0.12). The 2-year PFS in patients who proceeded to AHCT directly after receiving BV alone was 77%. Conclusions: Second-line BV is an effective bridge to AHCT that produces responses of sufficient depth to provide durable remission in conjunction with AHCT (clinicaltrials.gov: NCT01393717).

Efficient selection of genetically modified human T cells using methotrexate-resistant human dihydrofolate reductase.

Genetic modification of human T cells to express transgene-encoded polypeptides, such as tumor targeting chimeric antigen receptors, is an emerging therapeutic modality showing promise in clinical trials. The development of simple and efficient techniques for purifying transgene(+) T cells is needed to facilitate the derivation of cell products with uniform potency and purity. Unlike selection platforms that utilize physical methods (immunomagnetic or sorting) that are technically cumbersome and limited by the expense and availability of clinical-grade components, we focused on designing a selection system on the basis of the pharmaceutical drug methotrexate (MTX), a potent allosteric inhibitor of human dihydrofolate reductase (DHFR). Here, we describe the development of self inactivating (SIN) lentiviral vectors that direct the coordinated expression of a CD19-specific chimeric antigen receptor (CAR), the human EGFRt tracking/suicide construct, and a methotrexate-resistant human DHFR mutein (huDHFR(FS); L22F, F31S). Our results demonstrate that huDHFR(FS) expression renders lentivirally transduced primary human CD45RO(+)CD62L(+) central memory T cells resistant to lymphotoxic concentrations of MTX up to 0.1 µM. Our modular complementary DNA (cDNA) design insures that selected MTX-resistant T cells co-express functionally relevant levels of the CD19-specific CAR and EGFRt. This selection system on the basis of huDHFR(FS) and MTX has considerable potential utility in the manufacturing of clinical-grade T cell products.

Acute leukemia and myelodysplasia after adjuvant chemotherapy for breast cancer: durable remissions after hematopoietic stem cell transplantation.

BACKGROUND: Although secondary acute leukemias and myelodysplasia are the known complications of adjuvant chemotherapy for breast cancer, the treatment outcome of these secondary malignancies is presently unclear. We examined the clinical and pathological features as well as the treatment results of a series of patients with acute leukemia/myelodysplasia arising after adjuvant chemotherapy for breast cancer. PATIENTS AND METHODS: Patients referred to our institution during a 5-year period for treatment of acute leukemia/myelodysplasia and who had received adjuvant chemotherapy for breast cancer are included. Leukemia-free survival for the whole group and for patients who underwent hematopoietic stem cell transplantation (HSCT) was estimated. RESULTS: Fifteen women (14 with acute leukemia and one with myelodysplasia) were identified. Seven of 15 patients had received an anthracycline, cyclophosphamide and a taxane. Ten patients developed acute leukemia/myelodysplasia with a latency period of 2 years or less from initiation of chemotherapy. Although mixed-lineage leukemia (MLL) rearrangement was the commonest chromosomal abnormality (8 of 15 patients), various other chromosomal abnormalities were also detected. Twelve of 15 patients underwent HSCT (11 allogeneic and one autologous). Eleven of these 12 patients who underwent HSCT were in remission at a median follow-up of 20.4 months (range 4.4-53.3 months). CONCLUSION: Durable remissions can be achieved in patients who develop acute leukemia/myelodysplasia secondary to adjuvant chemotherapy for breast cancer and are able to undergo allogeneic HSCT. Our results indicate that HSCT should be an early consideration in the management of such patients who are suitable candidates for the procedure.

Allogeneic transplantation for ALL in adults.

Allogeneic transplantation is an effective treatment for adult patients with high-risk ALL, including patients in first or second remission. Although only a few studies have evaluated the optimal transplant regimens, the data would suggest that a TBI-based regimen results in better disease control. Although not as potent as it is in other hematologic malignancies, the GVL effect is an important component of achieving cure of ALL. Because of the toxicity of the fully ablative regimen, reduced-intensity transplants are being explored in older patients with ALL when the prognosis is especially poor with standard chemotherapy.

Reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation with fludarabine and melphalan is associated with durable disease control in myelodysplastic syndrome.

We retrospectively evaluated the outcome of reduced-intensity conditioning (RIC) followed by allogeneic hematopoietic stem cell transplantation (HCT) in 43 patients with myelodysplastic syndrome (MDS) or AML arising from MDS. All patients received fludarabine plus melphalan followed by an allogeneic HCT from an HLA-identical sibling (SIB: n=19) or unrelated donor (MUD: n=24). Median age was 58 years (range: 30-71). Diagnoses at transplantation were RA (n=8), RARS (n=1), RAEB (n=13), RAEB-T (n=6), or AML arising from MDS (n=15). Of 28 patients with MDS, two patients had low, 10 had intermediate-1, nine had intermediate-2 and seven had high-risk MDS by IPSS criteria. All patients initially engrafted with the median neutrophil recovery of 15 days (range: 9-27). The 2-year overall survival, disease-free survival, relapse and transplant-related mortality were 53.5% (CI 45.2-61.1), 51.2% (CI 43.3-58.5), 16.3% (CI 7.9-30.7) and 35.2% (26.4-45.7), respectively. Grade II-IV acute graft-versus-host disease occurred in 27 (63%) patients. There was no significant survival difference between SIB and MUD-HCT, but the relapse rate was higher among SIB donor recipients when compared to MUD (38.5 versus 7%, P=0.02). RIC with fludarabine plus melphalan was associated with durable disease control and acceptable toxicity in this high-risk cohort.

Redirecting T cells to eradicate B-cell acute lymphoblastic leukemia: bispecific T-cell engagers and chimeric antigen receptors.

Recent advances in antibody technology to harness T cells for cancer immunotherapy, particularly in the difficult-to-treat setting of relapsed/refractory acute lymphoblastic leukemia (r/r ALL), have led to innovative methods for directing cytotoxic T cells to specific surface antigens on cancer cells. One approach involves administration of soluble bispecific (or dual-affinity) antibody-based constructs that temporarily bridge T cells and cancer cells. Another approach infuses ex vivo-engineered T cells that express a surface plasma membrane-inserted antibody construct called a chimeric antigen receptor (CAR). Both bispecific antibodies and CARs circumvent natural target cell recognition by creating a physical connection between cytotoxic T cells and target cancer cells to activate a cytolysis signaling pathway; this connection allows essentially all cytotoxic T cells in a patient to be engaged because typical tumor cell resistance mechanisms (such as T-cell receptor specificity, antigen processing and presentation, and major histocompatibility complex context) are bypassed. Both the bispecific T-cell engager (BiTE) antibody construct blinatumomab and CD19-CARs are immunotherapies that have yielded encouraging remission rates in CD19-positive r/r ALL, suggesting that they might serve as definitive treatments or bridging therapies to allogeneic hematopoietic cell transplantation. With the introduction of these immunotherapies, new challenges arise related to unique toxicities and distinctive pathways of resistance. An increasing body of knowledge is being accumulated on how to predict, prevent, and manage such toxicities, which will help to better stratify patient risk and tailor treatments to minimize severe adverse events. A deeper understanding of the precise mechanisms of action and immune resistance, interaction with other novel agents in potential combinations, and optimization in the manufacturing process will help to advance immunotherapy outcomes in the r/r ALL setting.

Prevalence of conception and pregnancy outcomes after hematopoietic cell transplantation: report from the Bone Marrow Transplant Survivor Study.

We conducted a retrospective study to describe the magnitude of compromise in reproductive function and investigate pregnancy outcomes in 619 women and partners of men treated with autologous (n=241) or allogeneic (n=378) hematopoietic cell transplantation (HCT) between 21 and 45 years of age, and surviving 2 or more years. Median age at HCT was 33.3 years and median time since HCT 7.7 years. Mailed questionnaires captured pregnancies and their outcomes (live birth, stillbirth, miscarriage). Thirty-four patients reported 54 pregnancies after HCT (26 males, 40 pregnancies; eight females, 14 pregnancies), of which 46 resulted in live births. Factors associated with reporting no conception included older age at HCT (> or =30 years: odds ratio (OR)=4.8), female sex (OR=3.0), and total body irradiation (OR=3.3). Prevalence of conception and pregnancy outcomes in HCT survivors were compared to those of 301 nearest-age siblings. Although the risk for not reporting a conception was significantly increased among HCT survivors (OR=36), survivors were not significantly more likely than siblings to report miscarriage or stillbirth (OR=0.7). Although prevalence of conception is diminished after HCT, if pregnancy does occur, outcome is likely to be favorable. Patients should be counseled prior to transplant regarding strategies to preserve fertility.

Maintenance thalidomide following single cycle autologous peripheral blood stem cell transplant in patients with multiple myeloma.

Although autologous stem cell transplant is an effective therapy for patients with multiple myeloma and extends progression-free survival (PFS) and overall survival (OS), patients show a continued pattern of recurrent disease. Twenty-nine patients were enrolled in a phase II study investigating the tolerability and efficacy of maintenance thalidomide following single autologous peripheral blood stem cell transplant. Six to eight weeks after transplant, patients were started on maintenance thalidomide at 50 mg a day. The dose was gradually escalated to a target dose of 400 mg a day and continued until disease progression or 6 months after achieving complete remission (CR) for a maximum total duration of 18 months. At 6 months, 13 patients (45%) achieved CR or near complete remission (positive immunofixation without any evidence of disease). The estimated 2-year OS was 83% and PFS was 49%. Median tolerated dose of thalidomide was 200 mg a day. In conclusion, thalidomide as maintenance therapy is feasible and may improve outcome after single autologous stem cell transplant.

Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli.

Imatinib mesylate, a Bcr-Abl kinase inhibitor, has been very successful in the treatment of chronic myelogenous leukemia (CML). However, the majority of patients achieving cytogenetic remissions with imatinib treatment have molecular evidence of persistent disease, and residual BCR/ABL(+) progenitors can be detected. There is a need to develop new approaches that enhance elimination of malignant progenitors in imatinib-treated patients. Here we show that CML CD34(+) progenitors are sensitive to several apoptosis-inducing stimuli including the chemotherapeutic agents Ara-C and VP-16, radiation, arsenic trioxide, ceramide, growth factor withdrawal, and the death receptor activators TNFalpha and TRAIL. Bcr-Abl kinase inhibition by imatinib did not enhance sensitivity of CML progenitors to Ara-C, VP-16, ceramide, radiation or TRAIL-induced apoptosis but did enhance arsenic and TNFalpha-induced apoptosis. We further demonstrate that apoptosis was restricted to dividing cells, whereas nonproliferating BCR/ABL(+) CD34(+) cells were resistant to apoptosis induced by imatinib, Ara-C or arsenic, either alone or in combination. Resistance of quiescent CML progenitors to imatinib-induced apoptosis could contribute to persistence of residual malignant progenitors in imatinib-treated patients. Combination treatment with Ara-C or arsenic may not enhance targeting of nonproliferating CML progenitors. The assay described here may be useful for identifying agents targeting quiescent CML progenitors.

t(9;11)(p22;p15) in acute myeloid leukemia results in a fusion between NUP98 and the gene encoding transcriptional coactivators p52 and p75-lens epithelium-derived growth factor (LEDGF).

A t(9;11)(p22;p15) chromosomal translocation was identified in an adult patient with de novo acute myelogenous leukemia. Fluorescence in situ hybridization and Southern blot analysis mapped the 11p15 break-point to the NUP98 gene. Using 3' rapid amplification of cDNA ends, we have identified a chimeric mRNA that fused the NUP98 FXFG repeats in frame to the COOH-terminal portion of the gene encoding the transcriptional coactivators p52 and p75, also known as lens epithelium-derived growth factor (LEDGF). As expected, both NUP98-p52 and NUP98-p75 (LEDGF) chimeric mRNAs were detected by reverse transcription-PCR; however, the reciprocal p52/p75 (LEDGF)-NUP98 fusion mRNA was not detected. Our results demonstrate that this is the most 5' NUP98 fusion reported and reveal a previously unrecognized genetic target, the gene encoding p52/p75 (LEDGF).

Autologous bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma: value of augmented preparative regimens--a Southwest Oncology Group trial.

PURPOSE: To determine the toxicity and prognosis of patients with relapsed and refractory diffuse aggressive non-Hodgkin's lymphoma (NHL) who underwent an autologous bone marrow transplant (ABMT) using augmented preparative regimens, treated in a major cooperative group setting, and to examine prognostic factors for outcome. PATIENTS AND METHODS: Ninety-four patients with either chemosensitive (50 patients) or chemoresistant (44 patients) relapse, including 22 who failed induction chemotherapy, were treated with high-dose cyclophosphamide and etoposide with total-body irradiation (TBI) (67 patients) or an augmented carmustine (BCNU), cyclophosphamide, and etoposide (BCV) preparative regimen (27 patients) and an ABMT at 16 Southwest Oncology Group (SWOG) transplant centers. All relapsing patients were required to undergo a minimum of two courses of salvage therapy to determine chemosensitivity before transplant. Overall (OS) and progression-free survival (PFS) were determined and a Cox regression model was used to assess potential prognostic variables. RESULTS: Of the 94 eligible patients, there were 10 (10.6%) deaths before day 50 posttransplant because of infection (six deaths), hemorrhagic alveolitis (three deaths), or bleeding (one death). The median 3-year PFS and OS for the entire group was 33% and 44%. For those with chemosensitive disease the PFS and OS were 42% and 55%, whereas for those with chemoresistant disease the PFS and OS were 22% and 29%. The PFS and OS for those failing induction chemotherapy were 27% and 32%. The relapse rates within the first 3 years for the chemosensitive relapse, chemoresistant, and induction failure groups were 61%, 40%, and 59%, respectively. For both PFS and OS, only disease status at transplant was a significant factor in the multivariate Cox model. CONCLUSION: These results single institutional pilot trials exploring augmented preparative regimens. Patients undergoing transplantation for resistant disease, particularly those failing induction chemotherapy, appear to have an improved prognosis as compared with reports using standard preparative regimens. Therapies other than manipulation of standard preparative regimens appear to be required to decrease relapses following autotransplantation.

Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia.

The survival of patients with acute leukemia who do not achieve a remission with primary therapy is very poor. High-dose chemoradiotherapy followed by allogeneic bone marrow transplantation (BMT) has been shown to be effective therapy for patients with acute and chronic leukemia. Therefore, we determined the long-term disease-free survival of patients who did not achieve a remission and were then treated with high-dose therapy and bone marrow allografting from matched sibling donors. Twenty-one patients (median age, 28 years) who did not achieve a remission with induction chemotherapy were subsequently treated with allogeneic BMT. After BMT, 90% achieved a complete remission. Six died of complications of the therapy, and six patients relapsed between 27 and 448 days after BMT. Nine patients (43%; median age, 25 years) are alive between 556 and 4,174 days after BMT. The cumulative probability of disease-free survival at 10 years is 43%. This study suggests that allogeneic BMT can be an effective therapy to achieve long-term control of acute leukemia, even in those patients who do not achieve a remission with primary therapy.

Importance of bone marrow cytogenetic evaluation before autologous bone marrow transplantation for Hodgkin's disease.

Alkylating agents used either with or without radiation therapy have been associated with the development of myelodysplastic syndrome (MDS) and acute nonlymphoblastic leukemia (ANLL) after treatment of both malignant and nonmalignant disorders. This report describes seven patients with recurrent Hodgkin's disease (HD) evaluated for bone marrow transplantation (BMT) who developed chromosomal abnormalities, and emphasizes the importance of bone marrow cytogenetic studies before bone marrow harvest. Three patients with histologically normal bone marrow underwent autologous BMT and subsequently developed an MDS or ANLL. Four patients had the clonal abnormality detected before bone marrow harvest and did not proceed to BMT.

High-dose chemotherapy and stem-cell rescue in the treatment of high-risk breast cancer: prognostic indicators of progression-free and overall survival.

PURPOSE: To examine the predictive value of tumor- and treatment-specific prognostic indicators of relapse-free survival (RFS) and overall survival (OS) in patients with high-risk breast cancer (HRBC) treated with high-dose chemotherapy (HDCT) and stem-cell rescue. PATIENTS AND METHODS: Between June 1989 and September 1994, 114 patients with HRBC (stage II with > or = 10 axillary lymph nodes involved, stage IIIA, and stage IIIB inflammatory carcinoma) received adjuvant chemotherapy followed by HDCT with etoposide, cyclophosphamide, and either doxorubicin (CAVP) or cisplatin (CCVP). Variables analyzed included stage, tumor size, number of axillary nodes involved, grade and receptor status, and types of adjuvant chemotherapy and radiation therapy and HDCT. RESULTS: With a median follow-up time of 46 months (range, 23 to 93), Kaplan-Meier estimates of 3.5-year OS for stage II, IIIA, and IIIB HRBC are 82% (95% confidence interval [CI], 67% to 97%), 79% (95% CI, 67% to 91%), and 72% (95% CI, 53% to 91%); RFS estimates are 71% (95% CI, 56% to 85%), 57% (95% CI, 43% to 72%), and 50% (95% CI, 29% to 71%) irrespective of the HDCT regimen. In univariate analysis, the risk of relapse was lower for patients with progesterone receptor (PR)-positive tumors (risk ratio [RR], 0.43; 95% CI, 0.22 to 0.81; P = .01) and higher for patients with inflammatory carcinoma (RR, 2.20; 95% CI, 1.02 to 4.76; P = .05). OS was better for patients with PR (RR, 0.16; 95% CI, 0.05 to 0.55; P = .003) and estrogen receptor (ER)-positive tumors (RR, 0.42; 95% CI, 0.17 to 1.02; P = .05); OS was worse for patients with high-grade primary tumors (RR, 4.08; 95% CI, 1.21-13.7; P = .02). In multivariate analysis, PR positivity was associated with improved RFS (P = .01) and OS (P = .001). CONCLUSION: HDCT in selected patients with HRBC is safe and warrants further evaluation. Patients with receptor-negative, high-grade, or inflammatory tumors require improvement in their therapeutic options. Better assessment of the role of HDCT awaits completion of ongoing randomized trials.

Effect of low-dose prophylactic dopamine on high-dose cisplatin-induced electrolyte wasting, ototoxicity, and epidermal growth factor excretion: a randomized, placebo-controlled, double-blind trial.

PURPOSE: To evaluate the protective effect of low-dose dopamine given as continuous infusion in patients who undergo chemotherapy with the nephrotoxin cisplatin. PATIENTS AND METHODS: Forty-two patients who received high-dose cisplatin-containing chemotherapy entered a prospective, randomized, double-blind, placebo-controlled trial. Twenty-one patients received dopamine, and 21 received placebo. Patients were to receive either infusional dopamine 2 micrograms/kg/min over 48 hours or placebo. Cisplatin 125 mg/m2 was administered 12 hours after initiating dopamine (group D) or placebo (group P). This schedule was repeated twice, 1 week apart. Measurements of serum creatinine, urinary electrolytes and creatinine, urinary excretion of epidermal growth factor (EGF), ototoxicity, parameters of hematopoietic recovery, and duration of hospitalization were analyzed. RESULTS: We observed an increase in serum creatinine level to a peak of 1.9 mg/dL (range, 0.8 to 7.8) in the dopamine group, in comparison to 1.4 mg/dL (range, 0.9 to 3.3) in the placebo group (P = .04). Urinary magnesium excretion increased and EGF excretion decreased in both groups. Urinary sodium, chloride, and potassium excretion were increased in both groups, but more so in the placebo group. Dopamine had no measurable effect on hearing loss, duration of hospitalization, or hematopoietic recovery. CONCLUSION: The use of prophylactic dopamine increased peak serum creatinine levels relative to placebo and failed to prevent cisplatin-induced renal toxicity or ototoxicity. Determination of whether dopamine could reverse chemotherapy-induced renal damage would require a randomized prospective trial.

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.

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.

Killer Ig-like receptor (KIR) compatibility plays a role in the prevalence of acute GVHD in unrelated hematopoietic cell transplants for AML.

Killer Ig-like receptor (KIR) is a major cluster of the natural killer cell receptors and may play a role in the outcome of hematopoietic cell transplants. A total of 65 AML cases transplanted with T-replete hematopoietic cells from unrelated donors were retrospectively KIR-genotyped by a multiplex PCR method of our own design. The KIR gene frequency and genotype patterns in these 130 samples were consistent with the data in the literature. Based upon overall inhibitory and activating KIR genes in both donors and patients, we developed an algorithm to calculate a compatibility score for each transplant case as plus, zero or minus. Significantly higher incidence (18/20, 90%) of acute (a) GVHD (grade II-IV) was found in the transplant cases with plus scores than that (25/45, 56%) in the cases with zero or minus scores (P < 0.01). When the scores are sorted in the opposite way, fewer cases (13/26, 50%) of aGVHD were found in the transplants with minus scores than that (30/39, 77%) in the transplants with zero or plus scores (P < 0.05). The difference of aGVHD prevalence between the plus score and minus score groups is highly significant (P < 0.01). KIR genotype compatibility calculated by this algorithm may predict aGVHD incidence and be helpful in choosing donors.

The role of allogeneic bone marrow transplantation in the treatment of high-risk acute lymphocytic leukemia in adults.

Studies in the last decade show that most adults with acute lymphocytic leukemia (ALL) can achieve remission with intensive induction chemotherapy. Depending on the risk factors present at diagnosis in an individual patient, continued remissions range from less than 10% to more than 50%. The following factors have been shown to be predictive of relapse: high white cell count at diagnosis, age beyond 30, extramedullary disease at presentation, unfavorable chromosomal translocations, time longer than 6 weeks to enter remission, and use of less intensive chemotherapy for induction. Studies have been conducted to determine whether allogeneic bone marrow transplantation (BMT) could improve the outcome for patients with high-risk ALL when performed during first remission. These studies have shown that these patients have a 40% to 60% chance of disease-free survival. The current recommended strategy for patients with high-risk ALL in first remission is to undergo bone marrow transplantation prior to relapse. For those in second and subsequent remissions or those who do not achieve remission, allogeneic BMT still offers the best chance for cure of the disease.