Case

A 45-year-old man with no prior medical history presented to his primary physician complaining of a swelling on the right side of his neck. He had noticed the swelling three weeks earlier. He also reported weight loss despite a good appetite and a mild feverish feeling for one week. On examination, his physician found enlarged lymph nodes on both sides of his neck as well as in the right axillary area. Laboratory evaluation revealed anemia, leukocytosis with lymphocytopenia and a low albumin. The patient was referred to a local oncologist and further workup revealed that he had stage IV Hodgkin's lymphoma (HD) with bone marrow involvement. The patient underwent chemotherapy with Adriamycin^®, Bleomycin^®, vincristine and dacarbazine, the (ABVD) regimen. After three cycles of chemotherapy, his palpable lymphadenopathy, as well as mediastinal adenopathy on CT scan, had minimally decreased in size. Because of the resistant nature of the patient's lymphoma, other treatment options including dose intensive chemotherapy with stem cell transplant were discussed with the patient.

Q. In the era before hematopoietic stem cell transplantation, would this patient have a 25% chance of long-term survival (>5 years) with second line chemotherapy?

Yes.
No.

Answer: No.

Since the classic report by DeVita et al., advanced Hodgkin's disease (HD) has been known to be curable by chemotherapy. However, long-term survival with standard intensity salvage regimens for refractory disease has been uniformly poor. High doses, facilitated by autologous bone marrow transplantation (ABMT), can lead to better disease-free survival without improving overall survival.

Q. Are his age, gender, stage, hemoglobin, leukocytosis, lymphocytopenia and low albumin useful in determining his prognosis?

Yes.
No.

Answer: Yes.

The Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany defined an International Prognostic Index (IPI). The prognostic score represents the number of adverse prognostic factors present at diagnosis. Seven factors had similar independent prognostic effects: a serum albumin level of less than 4 g per deciliter, a hemoglobin level of less than 10.5 g per deciliter, male sex, an age of 45 years or older, stage IV disease (according to the Ann Arbor classification), leukocytosis (a white-cell count of at least 15,000 per cubic millimeter), and lymphocytopenia (a lymphocyte count of less than 600 per cubic millimeter, a count that was less than 8 percent of the white-cell count, or both). The score predicted the rate of freedom from progression of disease as follows: 0, or no factors (7 percent of the patients), 84 percent; 1 (22 percent of the patients), 77 percent; 2 (29 percent of the patients), 67 percent; 3 (23 percent of the patients), 60 percent; 4 (12 percent of the patients), 51 percent; and 5 or higher (7 percent of the patients), 42 percent. The authors concluded that the prognostic score may be useful in designing clinical trials for the treatment of advanced Hodgkin's disease and in making individual therapeutic decisions, but a distinct group of patients, at very high risk, could not be identified on the basis of routinely documented demographic and clinical characteristics.

Q. Is intensive chemotherapy with hematopoietic stem cell support better than conventional chemotherapy in a patient who has never achieved remission?

Yes.
No.

Answer: Yes.

Hodgkin's disease patients who never achieve complete remission with conventional chemotherapy (i.e., those with primary induction failure) have a poor prognosis. In a report from the Autologous Blood and Marrow Transplant Registry (ABMTR) on auto transplants for Hodgkin's disease in patients never achieving remission, some subjects who received high-dose therapy with autologous hematopoietic progenitor-cell infusion experienced prolonged progression-free survival. Probabilities of progression-free and overall survival at 3 years were 38% (95% confidence interval, 28% to 48%) and 50% (95% confidence interval, 39% to 60%), respectively. In multivariate analysis, "B" symptoms (fever, weight loss and night sweats) at diagnosis and poor performance score at transplantation were adverse prognostic factors for outcome.

Q. Is using more than one cycle of intensive chemotherapy with hematopoietic stem cell support to improve outcome in hematologic malignancies the current standard of care?

Yes.
No.

Answer: No.

There are conflicting data on the usefulness and safety of using so-called tandem transplants in multiple myeloma. Attal M, Harousseau JL et al. concluded that, as compared with single autologous stem-cell transplantation after high-dose chemotherapy, double transplantation improves overall survival among patients with myeloma, especially those who do not have a very good partial response after undergoing one transplantation. Segeren et al. found that intensified chemotherapy, followed by myeloablative therapy as first-line treatment for multiple myeloma, resulted in a higher CR (complete response) and a longer TTP (time to progression) when compared with intensified chemotherapy alone. However, it did not result in a better EFS (event-free survival) and OS (overall survival).

Conversely, Kyle concluded that preliminary data from three other randomized trials showed no convincing improvement in overall survival among patients receiving tandem transplantation, although the follow-up was too short for definite conclusions to be drawn.(1)

Recent reviews indicate that hematopoietic stem cell transplantation is the standard of care in multiple myeloma and that tandem transplant trial shows encouraging results.

These reviews all rely heavily upon a single successful trial.

Several single-arm trials have addressed the issue of tandem transplant in lymphoma and shown that prolonged survival is possible (though they have not compared the results to single transplant in a randomized way).

In an attempt to maximize dose intensity and achieve potential long-term remission, researchers at New York Medical College decided to evaluate the role of dose-intensive therapy using potentially non-cross resistant regimens of chemotherapy with autologous bone stem cell rescue.

The potentially non cross-resistant conditioning regimens were thiotepa, mitoxantrone and carboplatin (TMJ) followed by ifosphamide, carboplatin and etoposide (ICE) with autologous stem cell rescue in an attempt to maximize dose intensity and achieve long-term remission.

Patients with "sensitive" relapse of lymphoma were offered only one cycle of dose intensive therapy. All 76 consecutive patients who agreed to and participated in the protocol were reported regardless of whether they had one or two cycles of dose intensive therapy. Twenty-nine patients with HD and 47 with non-Hodgkin's lymphoma (NHL) underwent autologous stem cell transplant using TMJ as the conditioning regimen for the first transplant. Of these, 49 patients proceeded to the second transplant using ICE as the conditioning regimen. In 57 patients, only peripheral blood cells were used and in 11 patients both bone marrow and peripheral stem cells were used.

Twelve patients died from treatment-related toxicity. On an intent to treat basis, 32.14% of patients with HD refractory to initial or subsequent therapy survived long-term as opposed to 12.76% of patients with NHL. With a median follow-up of 83 months (range 25 - 110 months), the median disease-free survival of patients with HD was 7 months, as opposed to 2 months for patients with NHL. Multivariate analysis identified that patients with HD had a superior outcome if they were less than 35 years of age and did not have B symptoms. The authors concluded that dose-intensive chemotherapy with tandem transplantation is an option in patients with resistant/refractory lymphoma who have very limited treatment options and poor prognosis.

Q. Is there an advantage to using autologous transplantation as opposed to allogeneic transplantation?

Yes.
No.

Answer: Yes.

Autologous transplantation has the advantage of not requiring extensive typing and search. In addition, there are no graft versus host disease considerations.

Q. Are there disadvantages to using autologous transplantation?

Yes.
No.

Answer: Yes.

Autologous transplantation can potentially produce tumor contamination within the marrow source and it often lacks the immunologic potency, seen with allogeneic grafts, to destroy resistant tumor. Most centers now utilize autologous peripheral blood as a stem cell source.

Q. The patient presented here had Hodgkin's disease refractory to induction chemotherapy. According to the data from the Autologous Blood and Marrow Transplant Registry (ABMTR), would he have more than a 60% chance of being free of progression of disease three years later?

Yes.
No.

Answer: No.

The data from the ABMTR show that 38% of HD patients with induction failure, who subsequently undergo dose-intensive chemotherapy, have progression-free survival at 3 years.

However, the European group for Blood and Marrow Transplantation found that with a median follow-up of 37 months, the actuarial 3-year relapse-free survival rate is 24% for a group treated with conventional chemotherapy with consolidation and 55% for a group treated with autologous stem cell transplantation.

Q. Would the patient presented have at least a 50% chance of being alive 3 years after autologous stem cell transplantation?

Yes.
No.

Answer: Yes.

The data from the Autologous Blood and Marrow Transplant Registry are that the 3-year survival rate is about 50%.

Data from EBMT are also similar.

Q. Is autologous transplantation associated with severe toxicity?

Yes.
No.

Answer: Yes.

Although autologous stem cell transplantation does not cause the severe toxicity associated with the graft versus host disease seen with allogeneic stem cell transplantation, the drug treatment given prior to transplantation, called the conditioning regimen, is toxic. The ABMTR report did not include data on toxicity. However, the EBMT report indicated that excess toxicity from the conditioning regimen was a common cause of patients not being able to enter the randomized trial. The article by Ahmed et al. reported that 12 out of 76 patients in their series died as the result of treatment-related toxicity. In addition to the expected myelosuppression, nephrotoxicity with creatinine >2 mg/dl was seen in 5 patients. In 23 patients, the bilirubin rose to >2 mg/dl. Grade 3/4 infections (reference to NCI toxicity criteria) were noted in 59 patients. Twenty-eight patients had culture-proven sepsis with 5 patients experiencing septic shock. Five patients had infected central venous access devices. Two patients had grade 4 renal toxicity as a result of sepsis with multiorgan failure, and both of these patients died. Eight patients required intensive care unit admission within 100 days of dose intensive therapy. The median number of days in the intensive care unit was 11 (range 2-27).

Q. Is there any evidence that suggesting that two cycles of dose intensive therapy results in improved survival?

Yes.
No.

Answer: No.

Ahmed et al. reported that patients with HD who underwent two cycles of dose-intensive therapy had a superior overall and progression-free survival compared to those who did not (P<0.003). However, this may represent a self-fulfilling prophecy because the patients who are sicker and unable to tolerate a second cycle would not be offered one.

Q. Could radiation therapy be used as an alternative salvage therapy in the patient presented here?

Yes.
No.

Answer: No.

Radiation therapy is feasible for patients with localized disease. However, this patient already had bone marrow involvement and radiation therapy would lead to excessive myelotoxicity and require whole body radiation. In a retrospective review evaluating the results of autologous bone marrow transplantation (A-BMT) for patients with relapsed Hodgkin's disease (HD) who were potentially treatable by radical radiation therapy (RRT) because they had localized disease, Pezner et al. addressed the feasibility of radiation therapy as an alternative to high dose chemotherapy in candidates for autologous bone marrow transplantation. They concluded that long-term disease-free survival is frequently possible with either A-BMT or RRT in appropriately selected relapsed HD patients.

Q. Is there a role for allogeneic hematopoietic stem cell transplantation for this or similar patients?

Yes.
No.

Answer: Yes, but the role is still investigational at this time.

Allogeneic hematopoietic stem cell transplant (HSCT) has been evaluated in resistant lymphomas. The theoretical advantages of allogeneic HSCT are the avoidance of tumor cell infusion and avoidance of a possible graft-versus-lymphoma effect, both of which might reduce the probability of relapse after allogeneic HSCT. Analysis of patients with HD who underwent marrow transplantation at the Fred Hutchinson Cancer Research Center in Seattle revealed a lower relapse rate of human leukocyte antigen (HLA)-identical sibling transplants compared to autologous transplant (45 vs. 75% 5-year actuarial estimate). The differences in 5-year event-free survival (26 vs. 14%) and non-relapse mortality rates (53 vs. 43%) were not statistically significant. There was no association between acute graft-versus-host disease (GVHD) and relapse. Frequency of relapse at previously uninvolved sites was similar between autologous and allogeneic recipients.

Q. Is there a potential role for reduced intensity allogeneic hematopoietic stem cell transplantation (so called non-myeloablative HSCT)?

Yes.
No.

Answer: Yes, but once again this approach is investigational.

Non-myeloablative allogeneic HSCT is another approach performed with the intent of maximizing graft vs. tumor effect in the setting of reduced conditioning regimen toxicity. Occasionally, donor leukocyte infusion (DLI) must be performed at a later time for full engraftment. Two reports by Khouri et al. describe this form of transplant as promising. Carella et al. performed a trial to maximize both the effects of HSCT and the immunologic potential of allogeneic HSCT in patients with lymphoma. However, we must still point out that the toxicity from non-myeloablative HSCT remains a hurdle.

In conclusion, patients with refractory lymphomas represent a group of patients with limited treatment options and poor prognosis. Tandem transplantation using alternate non-cross resistant chemotherapy regimens offers hope to these patients. Larger trials using allogeneic HSCT and newer agents in the future will better define the treatment options for these patients.

Web Sites

Question 1

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=6892984

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2420444

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8096958

Question 2

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9819449

Question 3

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10080597

Question 4

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14695409

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12456509

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15509819

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15725911

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15561686

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15561295

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14695409

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10516678

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11029505

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10643540

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15621831

Question 7

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10080597

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11387366

Question 8

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10080597

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11387366

Question 9

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15621831

http://ctep.info.nih.gov

Question 10

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15621831

Question 11

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7642418

Question 12

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1991174

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8246023

Question 13

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9704734

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15197204

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11099321