Single and double autotransplants for relapsing/refractory Hodgkin s disease: results of two consecutive trials

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1 Bone Marrow Transplantation, (997) 9, Stockton Press All rights reserved /97 $2. Single and double autotransplants for relapsing/refractory Hodgkin s disease: results of two consecutive trials T Ahmed, DE Lake, M Beer, EJ Feldman, RA Preti, K Seiter, L Helson, A Mittelman, R Kancherla, J Ascensao 2, T Akhtar, P Cook 3, R Goldberg and M Coleman 4 Division of Oncology and Hematology, New York Medical College, Valhalla, NY; 2 Department of Medicine, University of Nevada, Reno, NV; 3 Hematology and Oncology Division, Brooklyn Hospital, Brooklyn, NY; 4 Division of Hematology and Oncology, Cornell University Medical College, New York, NY, USA Summary: ant to standard-dose chemotherapy, these patients often do not receive ABMT. Refractoriness to standard-dose treatment, To evaluate a strategy of one cycle of dose-intensive though, may not necessarily reflect total resistance to chemotherapy for patients with Hodgkin s disease in high-dose therapy, as suggested by occasional successes sensitive relapse and two cycles for those with refractory with dose-intensive therapy in resistant patients. We there- disease, 22 patients received dose-intensive fore decided to employ two sequential ABMTs to test in a chemotherapy followed by autotransplant in two consecutive polar fashion whether dose intensive treatment has a role studies. Patients with refractory disease were in the treatment of patients with ostensible resistance to offered a second transplant with different conditioning conventional-dose chemotherapy, and to compare their out- in the absence of progression or excessive toxicity. CR come to that of simultaneously referred patients with sensitive was present after treatment in 46% while 6% died in disease, treated with one autotransplant. In patients the peritransplant period. Of 4 patients with primary with refractory disease, we used two chemotherapeutically refractory disease and 42 with refractory relapse, 24 dissimilar regimens in order to exploit the theoretical bene- and 2 respectively received a second cycle. Of these 45 fit of any non-cross resistance between successive treatments. refractory patients, 2 were in CR and in PR after 3 Two consecutive studies with different con- the first cycle and of these in PR achieved a durable CR with the second transplant. The CR rate is 37% in patients with refractory relapse and 9% in those with primary refractory disease. At a median follow-up of 4 years, median survival is 45 months. Progressionfree survival of the refractory patients who could receive a second cycle was similar to that of patients with sensitive disease. A sequential transplant strategy is feasible. A subgroup of patients with refractory dis- ditioning regimens were performed, while maintaining the general study design. Patients and methods intensive therapy; refractory disease board of New York Medical College. All patients signed an approved, informed consent. Patients with disease resist- ant to initial or subsequent conventional chemotherapy were eligible to receive a second cycle of dose-intensive therapy, provided they had not progressed after the first transplant and had recovered sufficiently with respect to physiologic functions. Patients were classified as having sensitive relapse, refractory relapse, or primary refractory disease. Sensitive relapse was defined as a complete or partial response to conventional salvage chemotherapy prior to entry into the protocol; refractory relapse denoted absence of response to standard intensity salvage therapy despite previous Dose-intensive chemotherapy with autologous bone marrow transplantation (ABMT) is considered appropriate treatment for patients with relapsing Hodgkin s disease. 8 Relapsing disease, however, is prognostically different from partially responsive, non-responsive and progressive disease. 9 While all are usually classified under the broad rubric of refractory illness, relapsing patients are thought to have response and survival characteristics superior to that of the other categories, all of which are considered to be chemoresistant and truly refractory disease. Because of the perceived poor outcome of patients with disease resist- Correspondence: Dr T Ahmed, Division of Oncology/Hematology, New York Medical College, Valhalla, NY 595, USA Received 25 June 996; accepted 26 October 996 ease can achieve long-term survival after sequential Patient selection BMT. Keywords: Hodgkin s disease; double transplant; dose- All consecutive patients referred with histologically documented Hodgkin s disease that had not responded to or had relapsed after conventional-dose chemotherapy were eligible for dose-intensive treatment with autotransplantation according to protocols approved by the institutional review remission. Primary refractory disease denoted failure to achieve remission with initial chemotherapy.

2 45 Treatment Patients were treated prior to each autologous bone marrow transplant (ABMT) with the dose-intensive conditioning regimens outlined in the schema in Table. Study I: Patients in the first study (BEC-2-TAVE/TMJ), entering between February 987 and September 99, were given a dose-intensive conditioning chemotherapy regimen consisting of carmustine, 4 mg/m 2, etoposide, 8 mg/m 2 and cyclophosphamide, 5 g/m 2 (BEC-2). Those patients with primary refractory disease or refractory relapse received a second treatment with thiotepa, 9 mg/m 2, cytarabine, 3 6 g/m 2 and vinblastine,.4.6 mg/kg (TAVE). Neurotoxicity, both central and peripheral, was frequent with the TAVE regimen. Thus, patients with refractory disease entered later in the first study were given thiotepa, 75 mg/m 2, mitoxantrone, 4 mg/m 2 and car- boplatin, mg/m 2 (TMJ) as the second conditioning regimen. Hematopoietic growth factors were not available commercially for the first study. Non-mobilized peripheral blood progenitor cells (PSC) were given if a sufficient quantity of marrow could not be collected or in case of marrow involvement. All marrow and peripheral stem cells were collected as described elsewhere 4 prior to the first conditioning. bodies to cytomegalovirus (CMV) received blood products screened free of CMV. Filtered blood products were administered. Total parenteral nutrition was given for severe oral mucositis and continued until oral intake improved. All patients received prophylaxis for fungal, viral and Pneumocystis carinii infections. Broad-spectrum antibiotics were given for therapy of episodes of neutropenic fever. Prophy- lactic systemic antibiotics were not administered. Steroids were given to patients experiencing dyspnea and interstitial lung infiltrates following carmustine therapy in study I. Response assessment The following patient characteristics were registered on entry into the study: age, gender, disease histology, disease stage at diagnosis according to Ann Arbor criteria, 5 history of previous treatments and response, history of other diseases, physical findings, chemical and hematologic profile and tumor status, as determined no earlier than 2 weeks prior to conditioning treatment. Standard criteria for response evaluation were used. 6 However, radiographic abnormalities persistent and stable beyond 6 months in patients who had no other clinical evidence of disease were characterized as complete remission. Survival was calcu- lated from the first day of chemotherapy conditioning to the last day of follow-up. Study II: From September 99 to December 993, patients were initially treated with TMJ as described above. Data evaluation Those with refractory disease were given a second conditioning regimen of cyclophosphamide, g/m 2 and Data management was performed on commercially avail- etoposide, 8 24 mg/m 2 (EC). Total body irradiation able, customized data base and spreadsheet programs and (TBI), cgy, was additionally administered in the statistical calculations with the BMDP statistical package absence of prior radiotherapy to the spinal cord and of marwere compared by the 2 test and, where indicated, Fisher s and other programs designed ad hoc. 7 Categorical data row involvement. Hematopoietic growth factors were used for the collection of PSC and also to augment post-transgroup or paired Student s t-test after correction and testing exact test. Continuous parameters were compared by two- plant recovery. for distribution and comparability of the variance, or Ancillary treatment: All blood products were irradiated Mann Whitney s or Wilcoxon s non-parametric tests, as prior to infusion. Patients who were seronegative for anti- appropriate. 7,8 Survival curves were calculated with Kaplan Meier s product-limit method for overall survival and a life table method for progression-free survival; a log- Table Conditioning chemotherapy regimens rank test was used to compare the curves. 7,9 A test power (-Z beta ) of.8 or greater was required to declare a compari- BEC-2 son negative. 2 Carmustine (BCNU) 4 mg/m 2 day 5 Etoposide 8 mg/m 2 day 5 Cyclophosphamide 25 mg/m 2 days 5 and 4 TMJ Results Thiotepa 25 mg/m 2 days 7, 6 and 5 Mitoxantrone 4 mg/m 2 day 7 Carboplatin (JM8) 33 mg/m 2 days 7, 6 and 5 Patient characteristics and treatment Sargramostim (GM-CSF) 5 g/day starting day + Initial characteristics of the 22 patients are listed in Table TAVE 2. Sixty-nine patients with recurrent/relapsed disease were Thiotepa 25 mg/m 2 days 5, 4 and 3 entered into the first study, while 53 agreed to participate Cytarabine (Ara-C) 2 g/m 2 days 5, 4 and 3 in the second. Four patients did not undergo ABMT in our Vinblastine.4.6 mg/kg day 5 institution: two patients in the first study died prior to trans- EC plant while two in the second series, after undergoing mar- Etoposide 6 mg/m 2 days 8, 7 and 6 row collection, were transplanted elsewhere. All patients, Cyclophosphamide 25 mg/m 2 days 6, 5 and 4 ± total body irradiation Gy in 5 fractions over days 2 and except the two treated elsewhere, were included in the analysis. There were 68 males and 54 females. Median age Sargramostim (GM-CSF) 5 g/day starting day + at the time of protocol entry was 3 years (range, 6 6). Stage at initial diagnosis by Ann Arbor criteria was I in

3 Table 2 Patient characteristics Table 3 Treatment sequence by prior response 45 Total Study I Study II Early First Second loss transplant transplant Registered Age Study I BEC-2 None TAVE TMJ Range Sensitive relapse Median No evidence of disease 7 7 Gender Residual disease 3 3 Male Refractory relapse Female Primary refractory Initial stage I 2 Study II TMJ None EC II III Sensitive relapse IV No evidence of disease 5 5 Undetermined 5 4 Residual disease 4 4 No. of previous treatment regimens Refractory relapse Primary refractory Previous irradiation Yes Table 4 Response to treatment No No. CR PR PD Peri-BMT Response to prior treatment patients death Sensitive relapse No evidence of disease Radiographic abnormalities Study I Refractory relapse 4 3 Sensitive relapse 2 8 Primary refractory Refractory relapse Primary refractory % % 5% 2% Study II two patients, II in 38, III in 47 and IV in 3. The initial Sensitive relapse Refractory relapse staging procedure was deemed inadequate in five patients. Primary refractory Of the 39 patients with sensitive relapse, 3 had no radio- 53 4% 2% 28% 9% graphic or clinical evidence of disease following salvage therapy, and 26 had responsive relapsed disease with residual radiographic abnormalities. Of 83 patients with disease refractory to chemotherapy, 4 had responded to evaluation while one progressed in the peritransplant initial chemotherapy but not to salvage (refractory relapse), period. Of the 26 patients entering the study with residual and 42 had persistent or progressive disease after initial disease, 2 (8%, with 95% confidence interval 6 93%) induction therapy (primary refractory). There were more achieved complete remission (CR), three had partial patients with primary refractory disease in the first study. response (PR), one had progressive disease (PD) and one The number of patients who received the various conditioning died in the peritransplant period. Ten of the 3 patients regimens is shown in Table 3. The 2 patients who, after entering the study with no evidence of disease, with sensitive relapse in the first study received one treatment have been observed for 8 months or longer are still in with BEC-2 and 9 patients with sensitive relapse in remission. The 8-month progression-free proportion the second study had TMJ. Of 79 patients with refractory among those of the responding patients with sensitive disease who completed the first transplant, 34 received only relapse who had residual disease at entry is 5/23 (65%). one conditioning. Of these 34 patients, nine died in the peritransplant Median time to tumor progression, counting from day of period, progressed after the first ABMT, and transplant, was 8 months (range, 3 78) in the 35 patients 5 patients were not offered the initially planned second with sensitive relapse who had CR or PR at the end of treat- ABMT on account of excessive toxicity during the first ment. cycle. Forty-five patients went on to receive the second conditioning. Refractory disease: Of the 83 patients with refractory disease, 6 died in the peritransplant period, 23 (28%, with Response and response duration 95% confidence limits 8 38%) achieved CR and 5 PR. Progressive disease was noted in 23 patients. The difference Sensitive disease: Tumor response is indicated in Table 4. in response rates between patients with sensitive and refrac- Of the 39 patients with sensitive relapse, 3 had entered the tory disease was significant. Of the 38 patients with refractory study with no evidence of disease. Twelve of these patients disease who achieved either PR or CR, all of whom maintained their disease-free status at the end-of-treatment have been observed 8 months or longer, 23 patients (6%)

4 452 Double transplant in Hodgkin s disease are in continuing remission with a median progression-free survival of 5 months. Eleven patients with refractory disease received a second ABMT after achieving a less than complete response with the first cycle, and five of these patients had radiographic resolution of disease after the second treatment, while the other five remained long-term progression-free. These patients are alive without relapse, 8 months to 7 years (median, 29 months) after entry into the study and one, who was given BEC-2 followed by TMJ, died 6 months into the study of Pneumocystis carinii pneumonia contracted while under treatment with steroids for pulmonary fibrosis. a Survival The median follow-up of study patients is now 4 years, with a range of 4 87 months. Four patients were lost to follow-up 4 26 months after the start of treatment. The actuarial survival probability according to prior response status is shown in Figure. When the survival and progression-free survival of patients with sensitive relapse was compared to that of patients with refractory relapse or primary refractory disease, irrespective of the number of cycles administered, it was apparent that patients with sensitive relapse had a superior survival (P =.7). Patients with sensitive relapse receiving one transplant had a superior survival to those with refractory disease given two transplants, who in turn had a survival significantly superior to that of patients with refractory disease receiving one transplant only. Progression-free survival of patients with refractory disease receiving two cycles of dose-intensive therapy, compared to that of patients with sensitive relapse, was not different. This finding was clearly distinct from those patients with refractory disease who did not or could not receive the second cycle. The overall and progression-free survival probability for patients with sensitive relapse and those with refractory disease who could receive both transplants is plotted in Figure Months Figure Actuarial survival according to previous response status (( ) no evidence of disease; ( ) sensitive relapse; ( ) refractory relapse; (*) primary refractory) b Months Figure 2 Actuarial survival (a) and progression-free survival (b) prob- ability for patients with sensitive relapse ( ), patients with resistant dis- ease who received both of the planned transplants ( ), and those with resistant disease who received only one transplant ( ). Other characteristics that influenced survival were the initial disease stage and prior radiation therapy, while no significant differences were found when comparing the survival curves according to age, gender, number of treatment regimens prior to ABMT, and autotransplant treatment protocol. The survival curves of patients with sensitive relapse, regardless of whether there were initial radiographic abnormalities or not, were superimposable. Toxicity The major toxicities observed are outlined in Table 5. Two patients in each of the two studies were not evaluable for toxicity. One of the four patients who had evidence of myelodysplastic syndrome developed acute leukemia, two others were treated with allogeneic BMT, and one of them survives to date. Serious or lethal hepatitis and interstitial pneumonitis were more frequent in patients treated with the BEC-2 regimen. In addition to the eight patients developing severe pulmonary dysfunction after initial BEC-2 therapy, four died while clinically free of disease as a result of opportunistic pulmonary infections supervening in the face

5 Table 5 Severe toxicity for maximum doses of agents with dissimilar extramedullary toxicity. Repeated cycles of standard-dose combination Total Study I Study II chemotherapy are effective in the treatment of Hodgkin s disease but the use of repeated ABMT has not generally n = been explored. Pulmonary Hepatic Responsiveness to prior standard intensity chemotherapy, Vesical 4 4 which in our experience was confirmed to be the single Peripheral neuropathy 4 3 most important factor influencing response and survival fol- CNS 6 5 lowing autotransplant, was used as a means of determining Myalgias 9 9 Ileus 9 8 whether one or two cycles of dose-intensive therapy would Cardiac 8 7 be administered. As expected, patients with sensitive Myelodysplastic syndrome 4 3 relapse of Hodgkin s disease had a complete response rate Acute leukemia and survival superior to that of patients with refractory disease. However, patients undergoing two cycles of doseintensive therapy for refractory disease had a progressionfree survival comparable to that seen in patients with sensitive disease. of steroid therapy that was necessary to treat carmustine- This interesting phenomenon could represent a culling induced pneumonitis. Interstitial pneumonia was present in process whereby patients selected for a second ABMT have three cases of early death in the second study. a better prognosis than refractory patients in general, or it Prohibitive neurologic toxicity, severe myalgias requirmay represent a genuine alteration in the biology of the ing morphine, four cases of ileus/acute abdomen requiring surgery and four more with confusion, lethargy and cerebelthe latter possibility, a relevant observation is that of the disease by the second autotransplant itself. With regard to lar signs in patients receiving a second cycle of dose-intenpartial responders at the end of the first ABMT, half of sive therapy with TAVE led to the adoption of TMJ as the conditioning regimen for the second transplant. Neurologic whom were converted into complete responders, and all of toxicity was not seen with TMJ given as either the second whom, except in one case of fatal pulmonary toxicity, are or initial therapy. alive without relapse 8 months to 7 years after treatment. Except for the initial treatment of patients receiving Whether a delayed complete response would have been BEC-2, and neurotoxicity in patients receiving TAVE as a observed, had a second cycle not been given, is unclear. second conditioning, there was no difference in the type The fact is that such delay was not observed in responding and severity of recorded toxicity between the first and the patients who received a single ABMT. second autotransplants. Radiographic abnormalities persisted in some patients The average length of hospital stay for the first ABMT who had no clinical evidence of progression or active diswas 34 days (s.d. 9 days) for the first study and 25 (s.d. ease. Unchanged radiographic abnormalities are not always 2) for the second; a difference cannot be detected with indicative of active disease and must be correlated with the sufficient power. There was no difference between the dur- ation of hospital stay for the first and the second course of ABMT. clinical status of the patient. 25 We subjected several of these patients to biopsy and frequently found only fibrous tissue. Patients with refractory relapse of Hodgkin s disease or primary refractory disease are often not offered dose-intensive therapy. A subset of our refractory patients, in fact, Discussion achieved durable complete remissions with dose-intensive chemotherapy. This subgroup comprises patients who achi- Therapy for disseminated Hodgkin s disease represents a eve stabilization or response after the first transplant. Transtriumph of chemotherapy over a malignancy otherwise fatal plantation can thus identify those patients with disease in at least half of patients. 2 However, 5 2% of patients refractory to standard chemotherapy who are likely to benedo not respond to therapy and 22 25% relapse. 22,23 For fit from a second cycle. When such patients underwent a patients who relapse following conventional chemotherapy, second transplant in our program, their progression-free some success can be achieved with either an identical or survival was similar to that of patients with disease responalternative chemotherapy, depending on the duration of the sive to standard chemotherapy, a group that is traditionally prior complete remission. 9,22,24 considered to be likely to benefit from transplantation. In patients with disease responsive to conventional sal- A comparison of our results with those of other authors, vage chemotherapy, consolidation with dose-intensive therhowever, would be invalid because the term refractory apy and autologous transplantation is now being employed, disease, in various studies, is limited to those patients particularly for those patients relapsing in less than a year. who experienced progression of disease while receiving In patients with disease refractory at the outset or at relapse, standard-dose treatment. probability of success with dose-intensive therapy has been The question, whether double dose-intensive chemodeemed to be low. Such patients are often not even contherapy with autotransplant selects patients with a better sidered for dose-intensive therapy. We offered patients with prognosis or alters the course of the disease, should be refractory or relapsed disease two consecutive, noncrossaddressed by future controlled resistant chemotherapy combinations. This strategy allows studies. 453

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