by Dr. C.H. Weaver M.D. 5/2021
High-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) involves the administration of high doses of anti-cancer drugs and/or radiation therapy for the purpose of killing the cancerous lymphoma cells followed by the infusion of stem cells to “rescue” or restore bone marrow blood cell production.
Since conventional doses of chemotherapy cure some patients with NHL, doctors believed that giving higher more intensive dose chemotherapy regimens may cure more patients. Higher dose chemotherapy however kills critical red and white blood cells. To help rebuild the blood cells, patients undergo an autologous stem cell transplant after high-dose therapy.
It is important to understand that high-dose chemotherapy is the treatment for the lymphoma and damage to the stem cells in the bone marrow is a side effect. Fortunately, the bone marrow blood producing stem cells can be “rescued” or replaced with stem cells.
During an autologous stem cell transplant, stem cells are collected from the patient before high-dose chemotherapy is delivered. The stem cells are collected from the bone marrow or peripheral blood, processed, frozen and stored.
High-dose chemotherapy and autologous stem cell transplantation is a component of an overall treatment strategy utilized to treat many types of cancer. It is not a treatment of last resort and the role of stem cell transplantation in the management of lymphoma should be carefully planned following an initial diagnosis.
What do the studies show?
A direct comparison of conventional chemotherapy versus high-dose chemotherapy with ASCT in the treatment of patients with relapsed intermediate grade NHL demonstrated that nearly half of the patients who received the high-dose treatment survived five years or more without cancer compared to only 10% of the patients treated with conventional chemotherapy. This important clinical trial established high-dose chemotherapy with ASCT as the standard of care in the treatment of relapsed NHL.1
HDC and ASCT has remained the standard but the treatment landscape for NHL has evolved considerably. Rituxan has been added to CHOP chemotherapy establishing R-CHOP as the standard initial treatment for newly diagnosed lymphomas and multiple treatment strategies have been developed for recurrent NHL. The introduction of chimeric antigen receptor (CAR) T‐cell therapy changed the treatment landscape for relapsed/refractory lymphomas – demonstrating that 30% to 40% of heavily pretreated, relapsed/refractory DLBCL patients survive without cancer recurrence following CAR T cell therapy.7,8
There has also been an increased use of CAR-T cell therapy in individuals with an initial lymphoma recurrence as a result of the aforementioned trends but direct trials comparing ASCT and CAR-T as initial treatment for recurrent NHL have not been performed. There are considerable cost and side effect differences between these two treatment approaches and patients should discuss their role carefully with their doctor. Should CAR-T or ASCT be used to treat an initial recurrence? Should CAR-T be reserved for individuals who recur after ASCT and those who are unable to attain an initial remission at all?
In order to help provide some insight on the timing and role of HDC the Center for International Blood & Marrow Transplant Research (CIBMTR) evaluated the role of ASCT in patients with relapsed chemotherapy sensitive DLBCL based on the timing of relapse. (6) The CIBMTR found that for chemotherapy sensitive DLBCL patients who failed initial chemotherapy combined with Rituxan the clinical benefit of ASCT at the time of recurrence was similar to historical experience; producing a 44% to 52% cure confirming ASCT as a standard of care for chemotherapy sensitive relapsed DLBCL, regardless of the timing of relapse.
Additionally the CIBMTR evaluated patients with DLBCL who had chemotherapy sensitive and positron emission tomography/computed tomography (PET/CT) ‐ positive disease at the time of transplant who had achieved at least a partial response to treatment as measured by PET/CT. Patients were further analyzed based on the timing of relapse: early chemotherapy failure, with relapse occurring less than 12 months from diagnosis, and late relapse greater than 12 months following diagnosis.
Overall 41% for patients with relapsed chemotherapy sensitive DLBCL with PET/CT‐positive disease at the time of ASCT survived cancer free and were likely cured, regardless of the timing of chemotherapy failure. The cumulative 5‐year incidence of relapse was 48% among patients with early failure and 57% for those with late failure. Patients who experienced early chemotherapy failure were significantly younger, more likely to have stage III–IV disease at diagnosis, and to have primary refractory disease after first‐line therapy than individuals undergoing ASCT who failed initial treatment greater than 12 months from diagnosis.
The CIBMTR analysis supports the ongoing use of ASCT as treatment for patients with relapsed chemotherapy sensitive DLBCL, even for those patients having PET/CT‐positive PR at the time of transplant. CAR T‐cell therapy is an established standard treatment for patients with chemotherapy refractory DLBCL but more studies are needed to understand whether it should be used to treat chemotherapy sensitive DLBCL at the time of first recurrence.
Is there an age limit for HDC and ASCT?
There is no longer an actual age limit for undergoing HDC and ASCT and elderly patients with NHL can derive the same benefit as younger patients. ASCT is routinely successfully used to treat individuals in their 60's and 70's. Instead of actual age doctors focus more on an individuals underlying condition and other medical problems and weight these against the potential benefit of the ASCT. Older patients in particular however should consider ASCT at cancer centers that perform a high number of procedures annually and have more dedicated support.2
HDC & ASCT for Burkitts, small cleaved and highly aggressive NHL
Although clinical studies have not demonstrated a role for HDC and ASCT as initial treatment for intermediate grade and DLBCL, clinical trials support the use of HDC as the initial treatment for high grade aggressive NHL. High-dose chemotherapy should be considered an integral component of the overall treatment strategy of all high grade/aggressive non-Hodgkin’s lymphomas.
Consideration of the role of HDC in the treatment of a specific patient should be planned at initial diagnosis because HDC cures more patients than conventional-dose chemotherapy in many situations.
Autologous Stem Cell Transplant as Initial Treatment
High-dose chemotherapy can be incorporated into the initial treatment regimen or delivered to patients in complete remission after induction chemotherapy. For patients whose cancer is in complete remission after treatment with an aggressive multi-drug “leukemia type” chemotherapy regimen, the benefit of additional treatment with high-dose chemotherapy and stem cell transplantation is unknown. Patients in complete remission but at high risk of relapse may want to consider high-dose chemotherapy as additional treatment or have stem cells harvested and stored for use if the lymphoma relapses.
Patients in complete remission after treatment with conventional 3-4 drug “lymphoma type” chemotherapy regimens have a higher risk of cancer relapse and have received additional treatment with high-dose chemotherapy and stem cell transplantation in clinical trials to determine whether additional treatment can improve the chance of cure. Small numbers of patients have been treated with high-dose chemotherapy and stem cell transplantation in first remission and the chance of cure has been reported to be 70-90%. This appears to represent a substantial improvement over standard lymphoma treatments.
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
Resistant or recurrent high-grade or highly aggressive lymphomas are still curable, however there is no standard treatment. Conventional chemotherapy salvage regimens are able to produce a remission in a minority of patients. High-dose chemotherapy and autologous or allogeneic stem cell transplantation is probably the best “salvage” treatment, but may be difficult to perform.
In order to perform an autologous stem cell transplant, the patient must have previously collected and stored stem cells or be able to achieve a second remission. In order to perform an allogeneic stem cell transplant, a suitable stem cell donor must be identified. HLA typing for donor identification is time consuming and only 30-40% of patients will have a suitable stem cell donor identified.
High-dose chemotherapy and autologous or allogeneic stem cell transplantation has been reported to cure approximately 15% of patients with resistant lymphoma and 20%-30% of patients with Burkitt’s lymphoma still sensitive to treatment with chemotherapy.3
What About Follicular or low grade lymphoma?
Patients with low-grade follicular non-Hodgkin’s lymphoma are not cured with conventional therapy although many experience prolonged survival with successive treatments. Following conventional treatment of follicular lymphoma, the average duration of survival from diagnosis is approximately 8 years and from first cancer recurrence is approximately 5 years. High-dose chemotherapy with ASCT has been utilized to treat some patients with recurrent low-grade follicular lymphomas, but the potential benefit of improving long-term survival remains unclear due to the relatively long survival of conventionally treated patients.
Physicians at the Dana-Farber Cancer Institute have reported long-term results of treatment utilizing ASCT in 153 patients with low-grade follicular lymphoma who had failed initial chemotherapy. The minimum follow-up was 4 years and the longest is approximately 14 years.
At 8 years from treatment, 66% of patients survive, 44% without evidence of recurrent lymphoma. The treatment was well tolerated with only 1 patient dying from complications of therapy. Patients without evidence of lymphoma cells in the bone marrow at the time of marrow harvest had the best outcome following treatment with almost 70% surviving 12 years from diagnosis.
These physicians concluded that ASCT may prolong survival in patients with low-grade follicular lymphoma. Given the potential benefit and relative safety, high-dose therapy with autologous stem cell support should be considered early in the disease course for patients with low-grade follicular lymphoma.4
Strategies to Improve Autologous Stem Cell Transplantation
It is useful to think of HDC as a sequence of events. Improving the cure rates associated with HDC may result from intervening in one or more points in this sequence. The conventional sequence of delivering high-dose chemotherapy starts with reinduction chemotherapy followed by collection of stem cells. The next step is treatment with the high-dose chemotherapy preparative regimen, followed by infusion of the previously collected stem cells and then the post-transplant recovery period.
Zevalin® Used with Autologous Stem Cell Transplantation Effective for Chemo-Refractory, Aggressive NHL
The use of Zevalin® (Yttrium 90 Ibritumomab Tiuxetan) in conjunction with HDC and ASCT provides an effective treatment option for patients with aggressive NHL that has recurred following prior therapy.5
Zevalin is approved for treatment of recurrent or refractory indolent B-cell NHL. It uses a combination of mechanisms to target and kill cancer cells:
- Zevalin is comprised of ibritumomab, a monoclonal antibody that is attached to a radioactive substance called Yttrium 90 (90Y). The monoclonal antibody portion of Zevalin binds to proteins (CD 20 antigens) found only on the surface of B-cells. When Zevalin binds to the cancer cells, the immune system is stimulated to attack the cancer cells while the attached 90Y destroys these cells by spontaneous radiation emission.
- Researchers speculate that Zevalin may also produce anticancer effects through additional mechanisms not fully understood at present.
- This type of treatment not only provides anticancer treatment through separate strategies, but also delivers greater amounts of radiation to the cancer cells than external radiation therapy. Additionally, radiation exposure to normal cells is minimized.
Treatment with Zevalin includes initial administration of Rituxan® (rituximab), even in patients who have stopped responding to therapy with Rituxan alone. Rituxan is a monoclonal antibody that also binds to B-cells and is used commonly in the treatment of B-cell NHL. Zevalin is currently approved for the treatment of slow-growing (low-grade) NHL that has stopped responding to standard therapies. It continues to be evaluated in various stages and types of NHL.
Researchers from Israel conducted a clinical trial to evaluate the effectiveness of Zevalin in patients with NHL. This trial included 20 patients with aggressive NHL that had stopped responding to prior chemotherapy. Patients were diagnosed with either mantle cell NHL, diffuse large cell NHL, or transformed follicular NHL. The median age was 55 years, and the median number of prior treatment regimens was three.
Treatment for this trial included Zevalin used prior to high-dose chemotherapy, referred to as BEAM, and an autologous stem cell transplant.
- 14 patients achieved complete response (CR) and four achieved a partial response (PR).
- Estimated one-year survival is nearly 60%.
- Estimated one-year progression-free survival is 53%.
- The day 100 treatment-related mortality was 10%.
- There were no incidences of early infusion reactions.
The researchers concluded that the inclusion of Zevalin into high-dose chemotherapy regimens may improve disease-free survival and overall survival compared to high-dose chemotherapy and stem cell transplantation alone in patients with aggressive NHL that has stopped responding to standard therapies. Given the aggressive nature of NHL in patients in this trial, as well as the history of several prior treatment regimens, the authors are encouraged by these results.
Cell Processing: When stem cells are collected from a patient for infusion after high-dose chemotherapy, cancer cells may be present in the stem cell collection. Although the majority of cancer relapses after high-dose chemotherapy and autologous stem cell transplantation occur because the high-dose chemotherapy did not kill all of the cancer cells, it is possible that some patients may also relapse from infusion of the cancer cells “contaminating” the collected stem cells. Many techniques are being evaluated that effectively remove cancer cells from the stem cell collection. It is currently unknown whether enough cancer cells can be removed to decrease relapse rates. To learn more about techniques for removing cancer cells from the stem cell collection, select Autologous Stem Cell Collection and Processing.
Increased Dose Intensity of the High-Dose Chemotherapy Regimen: Since more treatment kills more cancer cells, increasing the intensity of treatment delivered can be accomplished by utilizing high doses of anti-cancer therapies or by delivering more than 1 cycle of high-dose treatment supported by stem cells. While increasing the intensity of treatment may kill more cancer cells, this approach may also damage normal cells and increase the toxicity or side effects.
Minimal Residual Disease: More patients achieve a complete remission following treatment with high-dose chemotherapy than treatment with conventional doses. Unfortunately, many patients who achieve a remission still experience a relapse of their cancer. This is because not all of the cancer cells were destroyed by treatment and may not have been detected. Doctors refer to this as a state of “minimal residual disease”. Many doctors believe that applying additional cancer treatments during the post-transplant recovery period when only a few cancer cells remain represents the best opportunity to prevent the cancer from returning.
Maintenance Therapy: The administration of Rituxan after an autologous transplant appears to delay time to cancer progression or prevent relapses. Other new drugs are being evaluated in the conventional treatment of patients with lymphoma and could be used after high-dose chemotherapy with autologous stem cell support.
- Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy‐sensitive non‐Hodgkin's lymphoma. N Engl J Med 1995; 333: 1540– 1545.
- Hosin, C., Saliba, RM., Okoroju G-J, et al. High dose chemotherapy and autologous hematopoietic progenitor cell transplantation for non hodgkin’s lymphoma in patients>65 years of age. Annals of Oncology [early online publication]. February 13, 2008.
- Milpied N, Deconinck E, Gaillard F, et al. Initial treatment of Aggressive Lymphoma with High-Dose Chemotherapy with Autologous Stem-Cell Support. The New England Journal of Medicine. 2004;350:1287-1295.
- Blood, Vol 94, No 10, pp 3325-3333, 1999
- Shimoni A, Zwass T, Oksman Y, et al. Ibritumomab Tiuxetan (90Y-Zevalin®) Combined with High-Dose Chemotherapy and Autologous Stem Cell Transplantation (SCT) in Patients with Chemo-Refractory Aggressive Non-Hodgkin’s Lymphoma. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. June 2006. Atlanta, GA.
- Hamadani M, Hari PN, Zhang Y et al. Early failure of frontline rituximab‐containing chemo‐immunotherapy in diffuse large B cell lymphoma does not predict futility of autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 2014; 20: 1729– 1736.
- Locke FL, Ghobadi A, Jacobson CA et al. Long‐term safety and activity of axicabtagene ciloleucel in refractory large B‐cell lymphoma (ZUMA‐1): a single‐arm, multicentre, phase 1–2 trial. Lancet Oncol 2019; 20: 31– 42.
- Schuster SJ, Bishop MR, Tam CS et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B‐cell lymphoma. N Engl J Med 2019; 380: 45– 56.