Daniel A. Filippa

Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin's lymphoma.

PURPOSE To evaluate a chemotherapy regimen that consisted of ifosfamide administered as an infusion with bolus carboplatin, and etoposide (ICE) supported by granulocyte colony-stimulating factor (G-CSF) for cytoreduction and stem-cell mobilization in transplant-eligible patients with primary refractory or relapsed non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS One hundred sixty-three transplant-eligible patients with relapsed or primary refractory NHL were treated from October 1993 to December 1997 with ICE chemotherapy at Memorial Sloan-Kettering Cancer Center. Administration of three cycles of ICE chemotherapy was planned at 2-week intervals. Peripheral-blood progenitor cells were collected after cycle 3, and all patients who achieved a partial response (PR) or complete response (CR) to ICE chemotherapy were eligible to proceed to transplantation. Event-free and overall survival, ICE-related toxicity, and the number of CD34(+) cells collected after treatment with ICE and G-CSF were evaluated. RESULTS All 163 patients were assessable for response, and there was no treatment-related mortality. A major response (CR/PR) was evident in 108 patients (66.3%); 89% of the responding patients underwent successful transplantation. Patient who underwent transplantation and achieved a CR to ICE had a superior overall survival to that of patients who achieved a PR (65% v 30%; P =.003). The median number of CD34(+) cells/kg collected was 8.4 x 10(6). The dose-limiting toxicity of ICE was hematologic, with 29.4% of patients developing grade 3/4 thrombocytopenia. There were minimal nonhematologic side effects. CONCLUSION ICE chemotherapy, with ifosfamide administered as a 24-hour infusion to decrease CNS side effects, and the substitution of carboplatin for cisplatin to minimize nephrotoxicity, is a very effective cytoreduction and mobilization regimen in patients with NHL. Furthermore, the quality of the clinical response to ICE predicts for posttransplant outcome.

Risk-Adapted Dose-Dense Immunochemotherapy Determined by Interim FDG-PET in Advanced-Stage Diffuse Large B-Cell Lymphoma

PURPOSE In studies of diffuse large B-cell lymphoma, positron emission tomography with [(18)F]fluorodeoxyglucose (FDG-PET) performed after two to four cycles of chemotherapy has demonstrated prognostic significance. However, some patients treated with immunochemotherapy experience a favorable long-term outcome despite a positive interim FDG-PET scan. To clarify the significance of interim FDG-PET scans, we prospectively studied interim FDG-positive disease within a risk-adapted sequential immunochemotherapy program. PATIENTS AND METHODS From March 2002 to November 2006, 98 patients at Memorial Sloan-Kettering Cancer Center received induction therapy with four cycles of accelerated R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by an interim FDG-PET scan. If the FDG-PET scan was negative, patients received three cycles of ICE (ifosfamide, carboplatin, and etoposide) consolidation therapy. If residual FDG-positive disease was seen, patients underwent biopsy; if the biopsy was negative, they also received three cycles of ICE. Patients with a positive biopsy received ICE followed by autologous stem-cell transplantation. RESULTS At a median follow-up of 44 months, overall and progression-free survival were 90% and 79%, respectively. Ninety-seven patients underwent interim FDG-PET scans; 59 had a negative scan, 51 of whom are progression free. Thirty-eight patients with FDG-PET-positive disease underwent repeat biopsy; 33 were negative, and 26 remain progression free after ICE consolidation therapy. Progression-free survival of interim FDG-PET-positive/biopsy-negative patients was identical to that in patients with a negative interim FDG-PET scan (P = .27). CONCLUSION Interim or post-treatment FDG-PET evaluation did not predict outcome with this dose-dense, sequential immunochemotherapy program. Outside of a clinical trial, we recommend biopsy confirmation of an abnormal interim FDG-PET scan before changing therapy.

Primary gastrointestinal lymphoma: A 30‐year review

The authors reviewed all cases of non‐Hodgkins lymphoma primarily involving the gastrointestinal tract treated at Memorial Hospital during the period from 1949–1978. Complete clinical records were available in 104 cases. Slides of original pathology specimens were available in 81 cases. Tumors were classified by Rappaport, Lukes‐Collins and modified Kiel classifications. All patients were staged retrospectively, using modified Ann Arbor staging. The primary tumor was in the stomach in 76 patients, in the small bowel in 15 and in the large bowel in 13. The life‐table survival for all patients at five years was 44% and for the 81 Stage I and II patients it was 53%. We found a trend toward improved survival for patients treated in the last decade (P = 0.05). Using Cox regression analysis, survival was found to be correlated with stage (P < 0.0001) and involvement of adjacent structures (P = 0.007). For Stage I patients, resection and radiation therapy were equally effective alone in controlling local tumor even though factors responsible for the selection of either treatment could not be identified. For Stage II patients, resection combined with radiation therapy controlled local disease better than either treatment alone. For Stage II, patient survival was correlated with the pattern of nodal involvement (P < 0.0001). Neither the choice of treatment (resection, radiation therapy, or resection with radiation therapy; P = 0.17) nor the involvement of resected margins (P = 0.22) affected survival. Among 81 Stage I and II patients, 68% had recurrences outside the primary field of treatment and 60% outside the abdomen. Systemic multiple modality therapy should be considered for patients at high risk for recurrence.

Primary pulmonary lymphomas. A clinicopathologic analysis of 36 cases

The clinical and pathologic findings in 36 patients with primary pulmonary non‐Hodgkins lymphoma were retrospectively evaluated. Each lymphoma was classified according to the Rappaport, Lukes‐Collins, Working Formulation, and Kiel criteria. Twenty‐one (58%) of the 36 patients had lymphomas classified as lymphoplasmacytic/lymphoplasmacytoid type of LP immunocytoma (LPI) according to the Kiel classification. The remainder of the patients (42%) had lymphomas distributed among the follicular center cell (FCC) types and immunoblastic sarcoma in the Lukes‐Collins classification. Survival of patients with LPI was significantly longer than that of patients with other types of lymphoma (88% versus 47% 5‐year actuarial survival estimate), and the LPIs were more often confined to the lung without hilar or mediastinal lymph node involvement. Seven (33%) of the 21 LPI evantually recurred after a mean follow‐up of 69 months, and 4 of these 7 developed serum paraproteins. Most of the patients with lymphomas other than LPI had persistent disease or an early recurrence. LPI, as described by Lennert, seems prone to arise in extranodal sites and to recur late. Measurement of serum immunoglobulins may be helpful in detecting recurrences of LPI.

ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35).

The subset of CD30-positive anaplastic large cell lymphomas (ALCL) with the NPM-ALK gene fusion arising from the t(2;5)(p23;q35) forms a distinct clinical and prognostic entity. Recently, various cytogenetic, molecular, and protein studies have provided evidence for the existence of several types of variant ALK fusions in up to 20% of ALK+ ALCL, of which only one, a TPM3-ALK fusion resulting from a t(1;2)(q25;p23), has so far been cloned. A cryptic inv(2)(p23q35) has been described as another recurrent cytogenetic alteration involving ALK and an unidentified fusion partner in some ALCL. In a screen for variant ALK gene fusions, we identified two ALCL that were negative for NPM-ALK by reverse transcriptase-polymerase chain reaction, but were positive for cytoplasmic ALK with both polyclonal and monoclonal antibodies to the ALK tyrosine kinase domain, consistent with ALK deregulation by an alteration other than the t(2;5) Case 1 was a T-lineage nodal and cutaneous ALCL in a 52-year-old woman, and Case 2 was a T-lineage nodal ALCL in a 12-year-old girl. FISH analysis confirmed ALK rearrangement in both cases. An inverse polymerase chain reaction approach was then used to identify the ALK translocation partner in Case 1. We found an in-frame fusion of ALK to ATIC, a gene previously mapped to 2q34-q35. We then confirmed by DNA polymerase chain reaction the localization of ATIC to yeast artificial chromosome (YAC) 914E7 previously reported to span the 2q35 break in the inv(2)(p23q35). FISH analysis in Case 1 confirmed rearrangement of YAC 914E7 and fusion to ALK. The ATIC-ALK fusion was confirmed in Case 1 and also identified in Case 2 by conventional reverse transcriptase-polymerase chain reaction using ATIC forward and ALK reverse primers. ATIC encodes an enzyme involved in purine biosynthesis which, like other fusion partners of ALK, is constitutively expressed and appears to contain a dimerization domain. ATIC-ALK fusion resulting from the inv(2)(p23q35) thus provides a third mechanism of ALK activation in ALK+ ALCL.

Cytogenetic analysis of 363 consecutively ascertained diffuse large B-cell lymphomas.

Cytogenetic analysis was performed on 363 biopsy specimens with histologically confirmed diffuse large B‐cell lymphoma (DLBCL), consecutively ascertained at the Memorial Sloan‐Kettering Cancer Center, New York, between 1984 and 1994. Among 248 samples successfully karyotyped, clonal chromosomal abnormalities were noted in 215 (87%). The salient cytogenetic features of DLBCL from this analysis comprised the following. Breakpoints clustered, in decreasing frequency, at 10 recurring sites: 14q32, 18q21, 1q21, 3q27, 1p36, 8q24, 3p21, 6q21, 1p22, and 22q11. Of these, deletion breaks affecting bands 3p21 and 1p22 and translocation breaks affecting bands 14q32, 3q27, and 1q21 were frequent and distinctive for this subset of lymphomas. Translocations affecting band 14q32 were noted in 110 cases (51%) of which 42 (20%) had t(14;18)(q32;q21), 21 (10%) had t(8;14)(q24;q32) or t(8;22)(q24;q11), 14 (6.5%) had t(3;14)(q27;q32) or t(3;22)(q27;q11), and 33 (15%) had other rearrangements of 14q32. Among 144 new translocations detected in the entire group, the breakpoints in 19 were recurrent and clustered at three sites: 1q21, 3q27, and 14q32. Regions of common cytogenetic deletions were identified at 11 sites, 1p36, 1p33–34, 1p31, 1q32, 3p25–26, 3p21, 3q21, 6q15, 6q21, 6q23–24, and 7q32, suggesting possible loss of candidate tumor suppressor genes associated with DLBCL development. Of these, only those at 6q21, 6q23, and 7q32 have previously been described in lymphoid neoplasms. The group of DLBCL with translocations affecting band 14q32 showed a significantly different pattern of additional cytogenetic changes compared to the group lacking such translocation. This new comprehensive cytogenetic characterization provides the basis for investigations aimed at identifying molecular mechanisms as well as the clinical impact of cytogenetic changes in DLBCL. Genes Chromosomes Cancer 25:123–133, 1999.

Primary follicular lymphoma of the gastrointestinal tract: A clinical and pathologic study of 26 cases

Although the gastrointestinal tract represents the most common site of extranodal lymphoma, primary follicular lymphoma of the gastrointestinal tract is an uncommon and poorly defined disease. We report the clinical and pathologic features of 26 patients with primary gastrointestinal follicular lymphoma. Ten of 26 patients (38.5%) were stage IIE, and 16 patients (61.5%) were stage IE. Of the 26 patients, 13 were female and 13 were male. The age range was 26–81 years (median 54.5 years). Abdominal pain was the most common presenting symptom, seen in 12 of 24 patients (50%). Nodularity of the mucosal surface was the most common endoscopic finding, seen in 10 of 14 patients (71.4%). The majority of cases (22 of 26, 84.6%) involved small bowel, four involved colorectum alone, and two involved the ileocecal valve. Within the small bowel the duodenum was the most commonly involved site (10 cases). Transmural involvement by follicular lymphoma was identified in 11 of the 16 patients who underwent surgical resection; five showed involvement of mucosa and submucosa only. The most common histologic grade was grade 1. Thirteen of 26 cases were grade 1, ten grade 2, and three grade 3. Twenty-one of 26 cases showed a predominantly follicular growth pattern, four mixed follicular and diffuse, and one predominantly diffuse. All cases were positive for CD20 and BCL2 and negative for CD3, CD5, CD23, CD43, and cyclin D1. Twenty-four of 26 were positive for CD10. Four of four cases showed cytogenetic or molecular genetic evidence of t(14;18). Initial treatment modalities included surgery plus chemotherapy (nine cases), surgery alone (seven cases), chemotherapy alone (four cases), observation alone (four cases), and chemotherapy and abdominal radiation (one case). One case presented with rectal polyps and was treated with polypectomy. A complete response was observed in 15 of 22 cases that received treatment, and of the 15 cases, five recurred 27–60 months after the initial diagnosis. Recurrence and progression were associated with histologic transformation to diffuse large cell lymphoma in one case. No significant correlation was identified between treatment response and various clinical and pathologic features. Overall, none of the 26 patients died of lymphoma. One patient died of a concomitant pancreatic carcinoma. Of the remaining 25 patients, 14 were disease free and 11 were alive with disease at a mean follow-up of 43 months. The estimated 5-year disease-free survival was 62%, and median disease-free survival was 69 months. The estimated 5-year relapse-free survival was 54%, and the median relapse-free survival was 63 months.

Primary lymphoma of the liver

Nine adult white men ranging in age from 27 to 76 (mean, 55 years) were treated for primary hepatic lymphoma between 1972 and 1986 at the Memorial Sloan‐Kettering Cancer Center. Six patients presented with right upper quadrant or epigastric pain or discomfort, and three patients complained of fatigue and lethargy. Fever and night sweats were evident in two, and two patients had lost weight. One patient was asymptomatic; the liver mass was detected during the work‐up for cancer of the prostate. Seven patients on whom computerized tomography was performed all had solitary masses in the liver although in three of them tumor had extended into both lobes as noticed at surgery. One had additional porta hepatic lymph node metastasis. Eight patients underwent an exploratory laparotomy; four had hepatic resection, and four had wedge biopsies of unresectable liver tumor. One patient had a percutaneous needle biopsy of the liver. Eight patients received combination chemotherapy. Six patients are alive, five of whom are in initial complete remission. All three patients who died had persistent or recurrent disease in the liver. The results of therapy and surgery to date in these and in other cases in the literature are encouraging.

Risk‐adapted autologous stem cell transplantation with adjuvant dexamethasone ± thalidomide for systemic light‐chain amyloidosis: results of a phase II trial

High‐dose melphalan (MEL) with autologous stem cell transplant (SCT) is an effective therapy for systemic AL amyloidosis (AL), but treatment‐related mortality (TRM) has historically been high. We performed a phase II trial of risk‐adapted SCT followed by adjuvant dexamethasone (dex) and thalidomide (thal) in an attempt to reduce TRM and improve response rates. Patients (n = 45) with newly diagnosed AL involving ≤2 organ systems were assigned to MEL 100, 140, or 200 mg/m2 with SCT, based on age, renal function and cardiac involvement. Patients with persistent clonal plasma cell disease 3 months post‐SCT received 9 months of adjuvant thal/dex (or dex if there was a history of deep vein thrombosis or neuropathy). Organ involvement was kidney (67%), heart (24%), liver/GI (22%) and peripheral nervous system (18%), with 31% having two organs involved. TRM was 4·4%. Thirty‐one patients began adjuvant therapy, with 16 (52%) completing 9 months of treatment and 13 (42%) achieving an improvement in haematological response. By intention‐to‐treat, overall haematological response rate was 71% (36% complete response), with 44% having organ responses. With a median follow‐up of 31 months, 2‐year survival was 84% (95% confidence interval: 73%, 94%). Risk‐adapted SCT with adjuvant thal/dex is feasible and results in low TRM and high haematological and organ response rates in AL patients.

Malignant lymphoma of the breast. A study of 53 patients

Fifty-three patients with non-Hodgkins lymphoma of the breast were reviewed and classified using four current classifications of lymphoma. All patients were female with a mean age of 57 years. The majority of patients had histiocytic or large-cell lesions and presented as clinical Stage I. The tumors were described clinically as primary in the breast, and mammary parenchyma was found in 79% of the diagnostic biopsy specimens. The other specimens showed lymphoma in mammary adipose tissue. Survival was not influenced by the presence or absence of breast parenchyma in the biopsy. Statistically significant survival differences were found to be related to stage at presentation as well as to tumor grade, using Kiel and Working Formulation categories. Patients with Stage I disease and those with low-grade lesions had a more favorable prognosis. No discernible factors, including stage or histologic findings, appeared to affect the recurrence rate.