Durable Disease-free Survival Research Articles

T-Cell Depleted (TCD) Hematopoietic Stem Cell Transplantation (HCT) For Adult Patients With Acute Myelogenous Leukemia (AML) In First and Second Remission: Long-Term Disease Free Survival(DFS) With a Significantly Reduced Risk Of Graft-Versus-Host Disease(GvHD)

IntroAllogeneic-HCT is recommended for AML patients (pts) in CR2, in CR1 with poor-risk cytogenetics, and should be considered for those in CR1 with intermediate-risk. Non-relapse mortality (NRM) and GVHD remain major causes of treatment failure. Ex vivo TCD can prevent GvHD but large case series have not been published. MethodsA retrospective chart review was conducted to evaluate 178 pts with AML in CR1 and CR2 undergoing TCD-HCT between 2001 and 2011. All pts received myeloablative-conditioning. The majority received ATG for graft rejection prophylaxis. Acute (A) and chronic(c) GVHD were assessed by standard criteria. No GVHD prophylaxis was administered post-transplant. Soybean agglutination+sheepRBC rosetting (sRBCR) was used for BM TCD. CD34+ selection +/- sRBCR was used for PBSC TCD. Pt characteristics were compared using Pearson's chi-squared and Fisher's exact tests. Prognostic factors relating to overall survival (OS) and DFS, including age, gender, leukemia etiology, cytogenetic-risk group, donor-type, TCD-method, conditioning-regimen, HLA match grade, HCT-specific comorbidity index and immune reconstitution were evaluated using log-rank test statistics. Differences in cumulative incidence (CI) rates were evaluated using Gray's test. Cox proportional-hazards regression was used to further adjust for pt risk factors for OS and DFS. ResultsPt characteristics and outcomes are summarized in Tables 1 and 2. Median follow-up of survivors is 52 mo (12-134). 177 pts engrafted. One died pre-engraftment, 7 developed late graft-failure (GF), and 3 are alive after a 2nd HCT. One yr incidence of aGVHD was low (grade 2-4 13%, 3-4 3%). Only 1 pt developed cGVHD by NIH consensus criteria. Univariate association between CR status (1 vs 2), OS and DFS was not statistically significant (p=0.17 and 0.16, respectively). After adjusting for HLA status, age, sex, cytogenetic risk, and regimen, CR2 pts had an increased risk of death (HR: 1.90 (1.14-3.16), p= 0.014). In CR1 pts, cytogenetics was associated with relapse incidence (p=0.003) and was highest in patients with adverse cytogenetics (31%, 95%CI 16-48) and <10% in intermediate I-II risk pts. Overall CI relapse at 1 and 2 yrs was 13% and 16%, respectively. Causes of death were: relapse (n=29), infection (n=25), GVHD (n=7), organ toxicities (n=5), GF (n=2) and other (n=7).Female gender was significantly associated with decreased OS and DFS (p<0.002 and 0.003, respectively). Two yr estimates of OS and DFS in females vs males was 51% vs. 71% and 49% vs. 69%, respectively. These differences were due to a higher NRM in females receiving the chemotherapy based regimen (p<0.001). Gender difference was not observed in pts receiving TBI-based regimens (p=0.599). This difference persisted after adjusting for other common prognostic factors in a multivariate model. For the entire group, 2yr OS and DFS was 67% and 62%, respectively. For CR1 pts, 2 yr OS and DFS was 70% and 64%, respectively (Fig.1). ConclusionThese results support the use of TCD HCT in AML pts in CR. Durable DFS and long-term OS can be achieved with low rates of GVHD without compromising the graft-vs-leukemia effect. [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Can a Durable Disease-Free Survival be Achieved With Surgical Resection in Patients With Pathological Node Positive Renal Cell Carcinoma?

Patients with isolated regional nodal metastases from renal cell carcinoma are a distinct cohort for which resection of involved lymph nodes may be therapeutic. We assessed the outcomes of patients treated at our institution with pathological node positive renal cell carcinoma without concomitant metastatic disease (T(any)N+M0). A total of 2,521 patients with nonmetastatic renal cell carcinoma (T(any)N(any)M0) of any histological subtype treated with nephrectomy were identified between 1995 and 2009. Pathological regional node positive disease in the absence of clinically detectable metastases (T(any)N(1-2)M0) was present in 68 patients (2.7%) and these patients formed our study cohort. Patients were assessed for timing and location of recurrence, disease specific survival and overall survival. Multivariate Cox regression analysis was performed to define factors predictive of recurrence and overall survival. Of the 68 patients with T(any)N(1-2)M0 renal cell carcinoma 22.1% were free of disease at a median followup of 43.5 months. In those patients experiencing recurrence, disease was detected within the first 4 months after surgery in 51% and was most commonly detected at multiple organ sites. The Kaplan-Meier estimated 5-year overall survival and disease specific survival was 37% and 39%, respectively. Predictors of a favorable outcome included an Eastern Cooperative Oncology Group performance status of 0, single node involvement, absence of sarcomatoid features and papillary histology. Nephrectomy with lymph node dissection can provide a durable disease-free survival in a proportion of patients with regionally advanced renal cell carcinoma and limited lymph node metastases.

Second-line age-adjusted International Prognostic Index in patients with advanced non-Hodgkin lymphoma after T-cell depleted allogeneic hematopoietic SCT

T-cell depleted allogeneic hematopoietic SCT (TCD-HSCT) have shown durable disease-free survival with a low risk of GVHD in patients with AML. We investigated this approach in 61 patients with primary refractory or relapsed non-Hodgkin lymphoma (NHL), who underwent TCD-HSCT from January 1992 through September 2004. Patients received myeloablative cytoreduction consisting of hyperfractionated total body irradiation, followed by either thiotepa and cyclophosphamide (45 patients) or thiotepa and fludarabine (16 patients). We determined the second-line age-adjusted International Prognostic Index score (sAAIPI) before transplant transplant. Median follow-up of surviving patients is 6 years. The 10-year OS and EFS were 50% and 43%, respectively. The relapse rate at 10 years was 21% in patients with chemosensitive disease and 52% in those with resistant disease at time of HSCT. Nine of the 18 patients who relapsed entered a subsequent CR. OS (P=0.01) correlated with the sAAIPI. The incidence of grades II-IV acute GVHD was 18%. We conclude that allogeneic TCD-HSCT can induce high rates of OS and EFS in advanced NHL with a low incidence of GVHD. Furthermore, the sAAIPI can predict outcomes and may be used to select the most appropriate patients for this type of transplant.

Reduced-intensity conditioned allogeneic haematopoietic stem cell transplantation results in durable disease-free and overall survival in patients with poor prognosis myeloid and lymphoid malignancies: eighty-month follow-up

The long-term outcome of patients with haematological malignancies treated with reduced-intensity conditioned allogeneic peripheral blood stem cell transplantation is not known. We report the outcome of 79 patients with poor-risk myeloid and lymphoid malignancies transplanted with reduced-intensity conditioning (RIC) regimens. The diagnoses include AML/myelodysplastic syndrome (n=43), non Hodgkin's lymphoma (n=30), Hodgkin's lymphoma (n=3), ALL (n=2) and CML (n=1). For the entire cohort, the disease-free survival (DFS) and OS were 61.2 and 35.7%, respectively. Twenty patients relapsed, 18 within the first three years, and 14 patients succumbed to progressive disease. Overall, 31 patients died from transplant-related complications within the first three years. Day 100 non-relapse mortality correlated with a higher total nucleated cell dose in the graft (odds ratio: 3.9). For those in CR at 3 years, the DFS and OS were 84.2 and 81.1%, respectively. Furthermore, of 43 patients with active disease at the time of transplantation, 16 remained in CR after 3 years. The majority of the long-term survivors were functioning independently. One patient died from a second malignancy. No post-transplant lymphoproliferative disorder was seen. In conclusion, durable disease control was achieved after RIC allogeneic stem cell transplantation for patients with advanced myeloid and lymphoid malignancies.

Are backup BM harvests worthwhile in unrelated donor allogeneic transplants?

The Cleveland Clinic blood and marrow transplant program has routinely performed 'backup' autologous harvests in unrelated recipients with hematological malignancies in remission, lymphoma without marrow involvement and CML in chronic phase. We reviewed all adult or cord unrelated donor (URD) transplants performed from January 1995 through September 2008 to evaluate the value of this procedure. Of 130 patients who had backup harvests, 15 (11%) had their backup harvests re-infused, all for graft failure. No patients undergoing fully ablative preparation and unmanipulated or T-depleted grafts from well-matched adult donors required infusion of backup marrow. Nine of 42 patients who underwent T cell grafts from partially matched or mismatched donors, five patients undergoing partially matched ablative transplants from adult donors or cord blood, and one patient undergoing non-myeloablative transplant required infusion of their back-up harvest. Five of 15 patients who received their backup marrow are alive in CR 2-11.6 (median 7.6) years from infusion. Two of these five were bridged to a second URD transplant; the other three showed durable disease-free survival without a second allogeneic transplant. Backup harvest is unnecessary for HLA well-matched myeloablative transplants, but may be useful in patients at higher risk of graft failure.

Outcomes among Patients with Relapsed Malignant Lymphoma after Allogeneic Hematopoietic Stem Cell Transplantation

Background: The management for recurrent lymphoma after allogeneic hematopoietic stem cell transplantation (HSCT) is challenging and it is not clear concerning its outcomes. Since potent graft-versus-lymphoma (GVL) effect is observed in some patients (pts) with follicular lymphoma (FL), peripheral T-cell lymphoma (PTCL) or adult T-cell leukemia/lymphoma (ATL) after allogeneic HSCT using reduced-intensity conditioning (Tanosaki et al, ASH 2006, BBMT 2008; 14:702), we hypothesized that it could also be exerted in relapsed patients. Hence, we retrospectively analyzed the outcomes among patients with lymphoma who relapsed after allogeneic HSCT.Patients and Methods: Between January 1999 and December 2007, 164 patients with refractory lymphoma, who were deemed incurable with standard or high-dose chemotherapy, underwent allogeneic HSCT in our single institution. Seventy-five pts remain in CR, 33 died associated with non-relapse mortality, 4 were lost follow-up, and 52 pts relapsed after the median of 71 days (range 1–1457), including 1 graft failure. Therefore, 51 pts were analyzed in this study.Results: Histological subtypes were diffuse large B-cell lymphoma (DLBCL) 13, ATL 12, lymphoblastic lymphoma 8, PTCL 7, FL 4, Hodgkin lymphoma (HL) 3, mantle cell lymphoma (MCL) 2, extranodal NK/T-cell lymphoma 2. Ten pts had an early relapse within 30 days, while 41 pts had a systemic (18 pts) or solitary relapse (23 pts) after the median of 98 days (range 33–1457). Relapse-oriented interventions included withdrawal of immunosuppressants (WIS), irradiation or surgical resection of localized lesion, donor lymphocyte infusion (DLI) and chemotherapy, which were used singly or in combination according to the clinical conditions; the breakdown and its outcomes were shown in Table. At the time of relapse, 46 pts (90%) had immunosuppressants, and WIS was first tried in 31 pts who didn't have GVHD. Overall survival rate (OS) at 2 years after relapse in pts with relapse >day 30 and ≤day 30 was 37±8% and 0% (p<0.001). Univariate analysis revealed that histological subtypes of PTCL or ATL, relapse after day 30, relapse after day 100 and RIST favorably affected OS after relapse. Notably, 9 pts (ATL 4, enteropathy-type PTCL 2, DLBCL 1, HL 1, MCL 1) survived after relapse and currently free of disease with the median follow up of 1394 days (range 288–2035). All of them experienced RIST and relapsed at the median of day 109 (range 56–550); 5 pts who relapsed at a solitary site received local irradiation (4) followed by resection of the residual lesion in 1 pt and WIS alone (1), and 4 pts with systemic relapse had WIS alone.Conclusions: These results suggested that some patients with chemo-refractory lymphoma with an immunogenic property could achieve a long durable disease-free survival after relapse without aggressive treatment modalities.Interventions and OutcomesTotalInterventionsResponseWISOpe/RTDLIChemoCR(CCR)*PRNC/PDRelapse >Day 30Solitary2310122110(5)011Systemic18150116(4)111Relapse ≤ Day 301060220(0)19Total5131125416(9)231*CCR; continuous complete remission after relapse.

Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation in Relapsed, Refractory, and Transformed Indolent Non-Hodgkin's Lymphoma

Few effective treatment options exist for chemotherapy-refractory indolent or transformed non-Hodgkin's lymphoma (NHL). We examined the outcome of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) in this setting. Sixty-two patients with indolent or transformed NHL were treated with allogeneic HCT from related (n = 34) or unrelated (n = 28) donors after conditioning with 2 Gy of total-body irradiation with or without fludarabine. Nine unrelated donors were mismatched for >/= one HLA antigen. Sixteen patients had histologic transformation before HCT. Twenty patients (32%) had progressive disease after previous high-dose therapy with autologous HCT. Median age was 54 years, and patients had received a median of six lines of treatment before HCT. Median follow-up time after HCT was 36.6 months. At 3 years, the estimated overall survival (OS) and progression-free survival (PFS) rates were 52% and 43%, respectively, for patients with indolent disease, and 18% and 21%, respectively, for patients with transformed disease. Patients with indolent disease and related donors (n = 26) had 3-year estimated OS and PFS rates of 67% and 54%, respectively. The incidences of grade 2 to 4 acute graft-versus-host disease (GVHD), grade 3 and 4 acute GVHD, and extensive chronic GVHD were 63%, 18%, and 47%, respectively. Among survivors, the median Karnofsky performance status at last follow-up was 85%. Nonmyeloablative allogeneic HCT can produce durable disease-free survival in patients with relapsed or refractory indolent NHL, even in this relatively elderly and heavily pretreated cohort. Outcomes were particularly good in patients with untransformed disease and related donors, whereas patients with transformed disease did poorly. Long-term survivors reported good overall functional status.

Treatment of Primary Cutaneous CD30+ Anaplastic Large-Cell Lymphoma With Radiation Therapy

Primary cutaneous CD30+ anaplastic large-cell lymphoma (CALCL) is a relatively rare and indolent variant of cutaneous T-cell lymphoma (CTCL). This report examines the response of localized disease to radiation alone. The Yale Cancer Center records were examined, and all patients with CTCL from January 1, 2001, to September 1, 2006, evaluated in the Department of Therapeutic Radiology were identified. Only those patients with localized or single CALCL lesions, no clinical evidence or history of lymphomatoid papulosis, no history of other CTCLs, no history of other skin disorders, lack of lymph node involvement, unambiguous pathology reports, and treatment with radiation alone were included. Eight patients were identified. Median age was 67 years, and gender was split evenly. Patients received radiation ranging from 34 to 44 Gy in 2-Gy fractions. Most patients (5 of 8) received 40 Gy, using 6 to 9 MeV electrons with 0.5 to 2 cm of bolus. All patients had a complete response. All patients were without evidence of disease at the most recent follow-up (median follow-up, 12 months). Radiation therapy was well tolerated, and the only recorded toxicity was Grade I to II dermatitis. Radiation therapy alone for localized CALCL is very well tolerated and clinical response is excellent. A dose of 40 Gy in 2-Gy fractions seems to be well tolerated and effective in inducing a complete response. Lower doses may be effective in achieving the same result, but data are not available. Longer follow-up is necessary before conclusions regarding durable disease-free survival can be made.

Prospective trial of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with advanced non-transitional cell (non-TCC) carcinomas of the urothelial tract

4542 Background: Non-TCC’s account for 5–10% of urothelial tract tumors and are each characterized by unique demographics, risk factors, and patterns of spread. A unifying feature of these malignancies is their aggressive course and poor outcomes with standard chemotherapeutic regimens. Given the rarity of these tumors, no prospective data are available to guide management. Methods: Patients with unresectable/metastatic adenocarcinoma, squamous cell, small cell, sarcomatoid, and poorly differentiated carcinomas of the urothelial tract were eligible. Treatment consisted of: Paclitaxel 200 mg/m2 IV on day 1, cisplatin 70 mg/m2 IV on day 1, ifosfamide 1500 mg/m2 IV on days 1–3 + mesna. GCSF was administered with each cycle. Treatment was recycled every 3 weeks for a maximum of 6 cycles. The primary endpoint was the response rate. Results: Twenty patients (pts) were enrolled with the following histologic types: adenocarcinoma 11/20, squamous cell carcinoma 8/20, small cell carcinoma 1/20. Pts received a median of 4 cycles (range, 1–6). The grade 3–4 toxicities included neutropenia (6/20), anemia (9/20), thrombocytopenia (4/20), confusion (1/20), seizure (1/20), neuropathy (1/20), renal insufficiency (2/20), fatigue (2/20), and hyponatremia (1/20). Thirteen of the 20 pts have died. The median survival for pts with adenocarcinoma is 24 months (95% CI 9.6–32.4) and with squamous cell carcinoma is 8.4 months (95% CI 5.3-NR). Five pts achieved durable disease-free survival (1+, 2+, 4+, 6+, and 8+ years) after ITP ± surgical consolidation. Conclusions: ITP is an active regimen in pts with advanced non-TCC’s of the urothelial tract. To our knowledge, this is the first prospective study of a chemotherapeutic regimen in this patient population. [Table: see text] [Table: see text]

Treatment of Oligometastases After Successful Immunotherapy

Local destruction of individual metastases by any of a number of effective modalities fails as a treatment for most patients with disseminated cancer because of the presence of either undetected micrometastases or simply too many lesions. The availability of a systemic therapy that could reduce the number of metastases to a manageable few would dramatically increase the utility of surgical metastasectomy or other locally ablative measures. Interleukin-2-based immunotherapy can serve exactly this function in some patients with renal cancer or melanoma. We review the effectiveness of surgery in treating limited relapses or residual disease in patients who have responded to systemic immunotherapy. These data indicate that a surprising percentage of such patients can enjoy durable disease-free survival after surgical removal of their oligometastases, and, for a significant minority, it appears to be curative.

Allogeneic or Autologous Stem Cell Transplantation (SCT) for the Treatment of Pediatric Patients with Non-Hodgkins Lymphoma (NHL).

Thirty six patients (pts) with NHL, aged 3.5–20.9 years (median 14.7 years) received an allo-SCT (n=21) or auto-SCT (n=15) at our institution between 12/82 and 12/04. Pathologic NHL classification included: lymphoblastic (n=12), Burkitt's (n=5), Large Cell (n=17) including ki-1 + (n=11), peripheral NHL (n=1), and undifferentiated NHL (n=1). Disease status at SCT was: first remission (CR1) (n=1), CR2 (n=15), CR3 (n=5), partial remission (n=7), relapse (Rel) or refractory (Ref) (n=8). Cytoreductive regimens were total body irradiation (TBI)-based for all but 3 pts in each of the allo-SCT and auto-SCT group. For the allo-SCT pts, donors were: matched related (n=15), mismatched related (n=1), and unrelated (n=5); graft-versus-host disease (GvHD) prophylaxis included T-cell depletion (TCD) (n=10) or post-BMT immunosuppression (n=11). Only one pt received a non-myeloablative allo-SCT. With one pt in the allo-SCT group lost to follow-up, 35 of 36 pts in the entire cohort were evaluable. The median follow up of the entire group was 21.5 months; it was 34 months and 20 months respectively for the allo-SCT and the auto-SCT groups. The overall survival (OS) and disease-free survival (DFS) were 56% and 54%, respectively. Ten of the 11 pts with ki-1 positive NHL are alive, disease-free after either allo-SCT (n=4) or auto-SCT (n=7) with a median follow-up of 26 months. The DFS for those patients transplanted in CR was 60% compared to 49% for those transplanted in either PR or Rel/Ref disease. Of the eight pts transplanted with progressive disease, 2 are alive, disease-free at 110 and 115 months; both pts post allo-SCT. For the allo-SCT group, the DFS was 52%. Seven pts relapsed, 4 of whom had Rel/Ref disease at the time of SCT. Four pts died of SCT-related complications. Five pts developed Grade II–IV aGvHD. For the auto-SCT group, the DFS was 53%. Two pts relapsed, and 2 pts died of toxicity. In summary, both allo-SCT and auto-SCT offer the prospect of durable disease-free survival for a significant proportion of pediatric patients with NHL after a first relapse or disease progression. In particular, those pts with ki-1-positive NHL had the most favorable outcome. As expected, pts transplanted in minimal residual disease achieved superior DFS.ResultsNCR/PRRel/RefRelapseTRMDFSAllo-SCT2111/4633%20%52%Auto-SCT1510/3213%13%53%

Primary lymphoblastic B-cell lymphoma of the cranial dura mater: a case report and review of the literature

Primary lymphomas of the cranial dura mater are rare. Mucosa-associated lymphoid tissue extranodal marginal zone lymphomas are the most common subtype of non-Hodgkin's lymphomas that present as primary cranial dura tumors. A 33 year-old male presented with a 3-month history of a growing lump in the right frontal area. Neuroimaging studies demonstrated an extra-axial, broad-based mass with a dural tail in the right frontal bone convexity. Biopsy led to the diagnosis of localized dural precursor B-cell lymphoblastic lymphoma. The patient was treated with a combination of chemotherapy and radiotherapy, achieving durable disease-free survival. This is the first report of precursor B-cell lymphoblastic lymphoma of dura mater. A review of the literature on primary lymphomas of cranial dura mater is presented.

The surgical management of muscle invasive bladder cancer: A contemporary review

Muscle-invasive bladder cancer is a potentially lethal disease with a high rate of cure if timely and effective therapy is applied while the disease is confined to the bladder or regional lymph nodes. Radical cystectomy is the gold standard to which all other local therapies including multimodality bladder-preserving strategies should be compared. Contemporary cystectomy combined with regional lymphadectomy may be performed with an acceptably low morbidity, provides unparalleled local control, and may result in durable disease-free survival even among patients with locoregional lymph node metastases. Refinements in surgical technique coupled with the expanded application of continent urinary diversion have resulted in excellent functional outcomes without compromising cancer control in properly selected patients. An increasing awareness of the importance of quality-of-life issues combined with an enhanced understanding of tumor biology have resulted in the surgical modifications which include an expanded role for lymphadectomy and preservation of uninvolved adjacent organs.

Reduced Intensity Allografts for Acute Myeloid Leukemia: Defining the Role of Conditioning and Donor Alloreactivity.

The role of reduced intensity allografting in the treatment of patients with acute myeloid leukemia (AML) is unclear. While more patients may survive the initial period following allografting in comparison to those receiving full intensity transplants, the risk of relapse may be greater, particularly in patients not in remission at the time of transplantation. Here we report the results of allogeneic transplants using either cytokine mobilized peripheral blood (PB) or bone marrow (BM) following a reduced intensity conditioning (RIC) regimen. 131 patients with AML were all conditioned with an identical regimen containing Cyclophosphamide at 120mg/kg iv over 2 days (days −3 and −2) followed by a single dose of total body irradiation at 550cGy on day −1. HLA-identical (HLA-ID) siblings donated cytokine mobilized PB to 62 recipients and unrelated donor (UD) BM was used for 69 patients. GVHD prophylaxis consisted of single agent cyclosporine (CSP) for recipients of HLA-ID allografts and CSP, methotrexate, and methylprednisolone in recipients of UD BM. The median age of recipients was 45 years (range 21–70), with 55 males and 76 females. 43 pts were in CR1, 33 in CR2, and 55 had relapsed (rel) or refractory (ref) disease. 59 of 69 recipients of UD BM were serologically identical with their donors at 6/6 antigens. There were no graft failures in either group.With a median follow-up of over 18 months, the results of transplantation are presented in the Table.Results of TransplantationClinical OutcomeAllograft SourceHLA-ID PBUD BMGrade 2–4 Acute GVHD42%51%Extensive Chronic GVHD57%61%Disease free survival (DFS) at 2 yearsCR149+/−10%39+/−12%CR219%+/−12%38+/−11%Rel/Ref17+/−8%0%For pts transplanted in CR1, the results are comparable to those observed following fully ablative conditioning, particularly since many pts were transplanted due to high risk karyotype. In CR2, outcomes following RIC were superior in recipients of UD BM compared to HLA-ID PB, possibly due to a greater graft versus leukemia effect. UD BM was ineffective in pts with rel/ref AML. Of interest, the 2 year DFS in pts with rel/ref AML following receipt of HLA-ID PB was 17% overall, but was 28% in those that developed any acute GVHD versus 0% in those that did not (P<0.02). In conclusion, while the role of RIC in the treatment of pts with AML requires further clarification, our findings suggest that in pts beyond CR1, clinical evidence of donor alloreactivity appears to be critical for ensuring durable DFS.

Successful Allogeneic Stem Cell Transplantation with Nonmyeloablative Conditioning in Patients with Relapsed Hodgkin's Disease Following Autologous Stem Cell Transplantation

Use of myeloablative preparative therapy and allogeneic stem cell transplantation (alloSCT) as salvage therapy for adult patients with relapsed hematologic malignancies after autologous stem cell transplantation (autoSCT) is generally unsuccessful due to very high treatment-related mortality rates. We report here the outcome of HLA-matched related donor alloSCT following nonmyeloablative preparative therapy in two patients with Hodgkin's disease, relapsed after autologous stem cell graft. Times from autoSCT to alloSCT were 9 and 11 months, respectively. Preparative therapy consisted of the following: oral busulfan, 4 mg/kg on days −6 and −5; intravenous (i.v.) cyclophosphamide, 350 mg/m 2 on days −4, −3 and, −2, and i.v. fludarabine, 30 mg/m 2 on days −4, −3, and −2; oral cyclosporin A (CyA) 5 mg/kg was begun on day −1 and i.v. methotrexate 5 mg/m 2 was delivered on days +1, +3, +5, and +11. Both patients achieved initial mixed chimerism as defined as >1% donor peripheral white blood cells and did not receive prophylactic donor lymphocyte infusions; both showed conversion to final full-donor chimerism. Stage I acute graft-vs.-host disease occurred in one patient and both achieved sustained complete response. One patient died on day 233 as a consequence of drug-induced pulmonary toxicity, whereas the other patient remains in continued complete remission 513 days after allograft. This nonmyeloablative alloSCT strategy was well tolerated, was completed entirely on an out-patient basis, and can result in durable disease-free survival among patients with Hodgkin's disease after failed autoSCT. Further follow-up and evaluation of additional patients are required to conclusively establish the role of this strategy in treatment of hematologic malignancies after autologous transplantation.

Successful allogeneic stem cell transplantation with nonmyeloablative conditioning in patients with relapsed hematologic malignancy following autologous stem cell transplantation

The use of myeloablative preparative therapy and allogeneic stem cell transplantation (alloSCT) as salvage therapy for adult patients with relapsed hematologic malignancy after autologous stem cell transplantation (autoSCT) is generally unsuccessful due to very high treatment-related mortality rates. We evaluated the outcome of HLA-matched related donor alloSCT following nonmyeloablative preparative therapy in 13 patients (median age, 38 years) with relapsed hematologic malignancies (Hodgkin's disease, n = 4; Hodgkin's disease and advanced myelodysplastic syndrome, n = 1; non-Hodgkin's lymphoma, n = 6; multiple myeloma, n = 2) after initial autoSCT. Median time from autoSCT to alloSCT was 12 months (range, 3-24 months); 6 patients had chemotherapy-refractory disease following autoSCT, 6 were in untreated relapse, and 1 had a partial response from salvage chemotherapy. Preparative therapy consisted of cyclophosphamide, 150-200 mg/kg; peritransplantation anti-thymocyte globulin; thymic irradiation (in patients who had not received previous mediastinal irradiation); and a very short course of cyclosporine as GVHD prophylaxis. All patients achieved initial mixed chimerism as defined by greater than 1% donor peripheral white blood cells. Seven patients, who had no evidence of GVHD, received prophylactic DLI beginning 5 to 6 weeks after transplantation for conversion of mixed chimerism to full donor hematopoiesis and to optimize a graft-versus-tumor effect. Six patients showed conversion to full donor chimerism and 1 lost the graft. Grade II or greater acute GVHD occurred in 9 patients. Seven patients achieved a complete response; 6 had no response. The median survival time of the 13 patients is currently 10 months (range, 3-39 months), with an overall survival probability at 2 years of 45% (95% confidence interval [CI], 19%-73%) and a disease-free survival probability at 2 years of 37.5% (95% CI, 12%-65%). Thus, this novel nonmyeloablative alloSCT strategy followed by prophylactic DLI was well tolerated and can result in durable disease-free survival among patients with advanced hematologic malignancies after a failed autoSCT. Further follow-up and evaluation of additional patients are required to conclusively establish the role of this strategy in the treatment of hematologic malignancies after an autologous transplantation.

LACK OF RETROPERITONEAL LYMPHADENOPATHY PREDICTS SURVIVAL OF PATIENTS WITH METASTATIC RENAL CELL CARCINOMA

Patients with metastatic renal cell carcinoma have a reported 5-year survival of 0% to 20%. The ability to predict which patients would benefit from nephrectomy and interleukin-2 (IL-2) therapy before any treatment is initiated would be useful for maximizing the advantage of therapy and improving the quality of life. A retrospective analysis of the x-rays and charts of patients treated at the National Institutes of Health Surgery Branch between 1985 and 1996, who presented with metastatic renal cancer beyond the locoregional area and the primary tumor in place, was performed. Preoperative computerized tomography or magnetic resonance imaging, or radiological reports if no scans were available, were used to obtain an estimate of the volume of retroperitoneal lymphadenopathy. Operative notes were used to evaluate whether all lymphadenopathy was resected or disease left in situ, or if any extrarenal resection, including venacavotomy, was performed. Mean survival rate was calculated from the time of nephrectomy to the time of death or last clinical followup. If patients received IL-2 therapy, the response to treatment was recorded. Mean survival and response rate for IL-2 were compared among patients in 3 separate analyses. Patients without preoperatively detected lymphadenopathy were compared with those with at least 1 cm.3 retroperitoneal lymphadenopathy. Also, the patients who had detectable lymphadenopathy were divided into subgroups consisting of all resected, incompletely resected, unresectable and unknown if all disease was resected. Each subgroup was compared with patients without detectable preoperative lymphadenopathy. Patients with less than were compared to those with greater than 50 cm.3 retroperitoneal lymphadenopathy. Patients undergoing extrarenal resection at nephrectomy (complex surgery) due to direct invasion of the tumor into another intra-abdominal organ were compared with those undergoing radical nephrectomy alone, regardless of lymph node status. Statistical analysis was done with the Mantel-Cox test for comparison of survival on Kaplan-Meier curves and with Fisher's exact test for response rates for IL-2. A total of 154 patients with metastatic renal cell carcinoma underwent cytoreductive nephrectomy as preparation for IL-2 based regimens. There were 82 patients with metastatic renal cell carcinoma and no preoperative retroperitoneal lymphadenopathy who survived longer (median 14.7 months) than the 72 with lymphadenopathy (median 8.5, p = 0.0004). Patients with incompletely resected, unresectable or an unknown volume resected had decreased survival compared to those with no retroperitoneal lymphadenopathy. A multivariate analysis of survival was performed evaluating the known prognostic indicators, performance status and tumor burden, as represented by the number of organs involved with metastases, and the new prognostic factor, lymphadenopathy. Lymphadenopathy was more closely associated with survival than performance status, and appeared to be a new prognostic variable. Patients with and without retroperitoneal lymphadenopathy at initial presentation had similar rates for treatment with IL-2 (54% for both groups). Of the 82 patients with no lymphadenopathy 11 (13%) had long-term survival greater than 5 years. Of the 6 complete responses to IL-2, 5 occurred in this group. Only 1 other patient with incompletely resected retroperitoneal lymphadenopathy survived longer than 5 years. No significant difference in survival was seen between patients who did or did not undergo complex surgery. Patients who presented with metastatic renal cancer and retroperitoneal lymphadenopathy had a shorter survival than those with no detectable retroperitoneal lymphadenopathy. It is warranted to continue to perform complex extrarenal resection during nephrectomy since no significant difference in the response rate for IL-2 or mean survival compared with those of patients undergoing nephrectomy alone is currently detectable.

Retinoic acid receptor fusion proteins: friend or foe

Acute promyelocytic leukemia (APL) is characterized by a block in differentiation of hematopoietic cells at the promyelocytic stage of development. This disease is uniquely sensitive to treatment with pharmacological doses of all- trans retinoic acid (ATRA), and the combination of ATRA with chemotherapy has improved the durable disease-free survival in these patients to up to 80%. APL is characterized by chromosomal translocations that lead to the fusion of the retinoic acid receptor-α (RARα) to various partner genes. RARα functions as a ligand-inducible transcription factor and the aberrant RARα fusion proteins contribute to leukemic transformation by dominant inhibition of the expression of target genes that are important for cellular differentiation. This may at least in part be explained by an abnormally strong interaction with corepressor proteins leading to deacetylation of DNA and silencing of target genes. Most RARα fusion proteins can still be induced to transactivate genes, but only at very high doses of ligand, explaining why pharmacological doses of ATRA are necessary to obtain a therapeutic effect in these patients.

The role of high-dose chemotherapy and stem cell rescue in the treatment of malignant brain tumors: a reappraisal.

The outcome for children with malignant brain tumors has improved modestly in recent years. Notable is the improved 5-yr disease-free survival for those children with 'standard-risk' medulloblastoma and other primitive neuro-ectodermal tumors (PNET) (i.e. tumors without neuraxis dissemination at presentation). For other children with newly diagnosed malignant brain tumors, especially in the absence of radical surgical resection, the outcome remains poor despite surgery, irradiation and conventional chemotherapy. Patients whose tumors recur despite initial therapy continue to experience a dismal outlook with these conventional strategies of treatment. In an attempt to improve the outlook for such brain tumor patients with poor prognoses, strategies utilizing high-dose (potentially myeloablative) chemotherapy with autologous stem cell rescue have been developed. These studies, conducted initially in patients with recurrent tumors, were then extended to patients with newly diagnosed malignant gliomas and brain-stem tumors, as well as to young children with various malignant brain tumors at diagnosis in an attempt to avoid irradiation to the brain. The results of several of these studies are summarized, updating information reviewed in an earlier summary in 1996, demonstrating durable disease-free survival for a proportion of patients with recurrent malignant gliomas and medulloblastomas/PNET, as well as encouraging data in some of those patients with newly diagnosed brain tumors.

New chemotherapy regimens for metastatic bladder cancer

M-VAC remains the standard of care for metastatic transitional cell carcinoma (TCC), but its limitations include significant toxicity and infrequent durable disease-free survival. Recent investigation has focused on the identification of novel chemotherapeutics with single-agent activity in metastatic TCC and on their incorporation into more active combination regimens. Paclitaxel, gemcitabine and ifosfamide are among the most active new agents. Numerous phase II trials of novel combinations have yielded promising preliminary results. Longer follow-up and results from randomized trials will be necessary to determine the impact of newer chemotherapy regimens on survival.