Hematopoietic Cell Transplantation for Hodgkin's Disease

Number: 0495

Policy

  1. Autologous Hematopoietic Cell Transplantation

    Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of Hodgkin's disease (HD) when the member meets the transplanting institution's selection criteria.  In the absence of such criteria, Aetna considers autologous hematopoietic cell transplantation medically necessary for the treatment of HD when both of the following selection criteria are met:

    1. The member is in primary induction failure or beyond first remission; and
    2. The member is without serious organ dysfunction based on the transplanting institution's evaluation.

  2. Allogeneic Hematopoietic Cell Transplantation

    Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the treatment of members with relapsed HD (including members who have relapsed or have had persistent disease from an autologous hematopoietic cell transplant) or primary refractory HD when the member meets the transplanting institution's selection criteria.  In the absence of such criteria, Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the treatment of members with relapsed or primary refractory HD when both of the following selection criteria are met:

    1. The member is in primary induction failure or beyond first remission; and
    2. The member is without serious organ dysfunction based on the transplanting institution's evaluation.

    Note: Aetna considers non-myeloablative allogeneic hematopoietic cell transplantation ("mini-transplant," reduced intensity conditioning transplant) medically necessary for the treatment of members with relapsed HD (including members who have relapsed or have had persistent disease after an autologous hematopoietic cell transplant) or primary refractory HD when they are eligible for conventional allografting.

  3. Tandem Transplants

    Aetna considers tandem (also known as sequential) transplants experimental and investigational for the treatment of HD because insufficient evidence of its effectiveness and safety for this indication.

Note: Relapse is the re-appearance of disease in regions of prior disease (recurrence) and/or in new regions (extension) after initial therapy and attainment of complete response.

See also CPB 0823 -  Brentuximab (Adcetris).

Background

Hodgkin's disease (HD) is an enigmatic lymphoid malignancy whose cell of origin has remained a mystery since the disease was first described in 1825.  The hallmark of the disease is effacement of the normal lymph node architecture by a heterogeneous infiltration of normal appearing lymphocytes, plasma cells, eosinophils and fibroblasts.  The one characteristic component, and presumably the malignant component, is the Reed Sternberg cell (or one of its variants), a large binucleate cell with prominent nucleoli.  Hodgkin's disease is subdivided into 4 subtypes:
  1. lymphocytic predominant (15 % of cases),
  2. nodular sclerosing (70 %),
  3. mixed cellularity (10 %), and
  4. lymphocyte depleted (5 %). 
Both the lymphocyte predominant and nodular sclerosing variants are more common in adolescents and young adults.  Mixed cellularity and lymphocyte depleted are more common in older patients and frequently present with advanced disease.

The following staging system for HD recognizes the fact that HD is thought to typically arise in a single lymph node and spread to contiguous lymph nodes with eventual involvement of extranodal sites.  The staging system attempts to distinguish patients with localized HD who can be treated with extended field radiation from those who require systemic chemotherapy.

Staging for Hodgkin's Disease

Stage I: 

Involvement of a single lymph node region or a lymphoid structure such as the spleen, thymus, Waldeyer's ring (I) or involvement of a single extra-lymphatic organ or site (IE)

Stage II: 

Involvement of 2 or more lymph node regions on the same side of the diaphragm (hilar nodes, when involved on both sides, constitute Stage II); localized contiguous involvement of only 1 extra-nodal organ or site and lymph node region on the same side of the diaphragm (IIE).  The number of lymph node regions involved should be indicated by a subscript (e.g., II3)

Stage III: 

Involvement of lymph node regions or structures on both sides of the diaphragm (III), which may also be accompanied by involvement of the spleen (IIIS) or by localized contiguous involvement of only 1 extra-nodal organ site (IIIE) or both (IIIE+S).  These patients are further subdivided as follows:

III1:  with or without involvement of splenic, hilar, celiac, or portal lymph nodes

III2:  with involvement of paraaortic, iliac, and/or mesenteric lymph nodes

Stage IV: 

Diffuse or disseminated Involvement of 1 or more extra-nodal organs or tissues, with or without associated lymph node involvement, or isolated extra-lymphatic organ involvement with distant (non-regional) nodal involvement 

Additional Designations Applicable to any Disease Stage

A:  No symptoms
 
B:  Unexplained fever (temperature greater than 38° C), drenching night sweats, unexplained weight loss of greater than 10 % body weight within the preceding 6 months.  Pruritus alone does not qualify for B classification, nor does a short febrile illness associated with an infection
 
X:  Bulky disease (a widening of the mediastinum by greater than 1/3 or the presence of a nodal mass with a maximal dimension greater than 10 cm)
 
E:  Involvement of a single extra-nodal site that is contiguous or proximal to a known nodal site
 
CS:  Clinical stage
 
PS:  Pathological stage (as determined by laparotomy)

Staging of HD includes not only the sites of involvement, but also other factors described by the letters A, B, X, E above, i.e., a patient could have Stage IIB HD, indicating involvement of 2 or more lymph node groups on the same side of the diaphragm with the presence of systemic symptoms.  Those patients initially considered candidates for radiation therapy alone may undergo a staging laparotomy to determine if the disease is truly localized or not.

Treatment of HD involves the use of radiation therapy alone (for Stage I and II disease), the use of chemotherapy (for Stage IIIB and IV), or combined radiation and chemotherapy (for patients with bulky disease and for some patients with Stage IIIA disease).  Radiation therapy typically consists of treatment not only of the involved sites, but also lymphoid regions adjacent to the involved areas and prophylactic treatment to uninvolved areas.  This frequently takes the form of mantle irradiation to the mediastinum and an "inverted Y" irradiation of the periaortic lymph nodes, extending down to encompass the pelvic lymph nodes.  Prolonged relapse free survival in patients with Stage IA or IIA treated with total nodal irradiation is estimated at 82 %.

Despite the generally favorable results of irradiation and chemotherapy, relapses can occur in up to 40 % of those patients with advanced (Stage III or IV) disease treated with chemotherapy.  In many instances, relapsed HD remains sensitive to the original chemotherapy used, indicating that relapses may not be related to the development of chemoresistance, but instead point to the importance of adequate dosing of chemotherapy.  This observation also forms the rationale for high dose chemotherapy (HDC).

High dose chemotherapy bone marrow or peripheral stem cell transplant (autologous or allogeneic) is a treatment option for selected patients with HD.  The basic concept behind HDC is a combination regimen of marrow ablative drugs which have different mechanism of action to maximally eradicate the malignant cells, and non-overlapping toxicity such that the doses can be maximized as much as possible.  Total body irradiation (TBI) is an additional variable.  Patients with the disease who are responsive to standard doses of chemotherapy, and are either asymptomatic or have a good performance status and who do not have any serious co-morbidities are considered optimal candidates for HDC.

Autologous bone marrow transplant (ABMT) or peripheral stem cell transplant (ASCT) permits the use of chemotherapeutic agents at doses that exceed the myelotoxicity threshold; consequently, a greater tumor cell kill might be anticipated.  It has been suggested that the resultant effect is greater response rate and possibly an increased cure rate.  Autologous bone marrow transplant entails the patient acting as his/her own bone marrow donor.  The patient's marrow is harvested via aspiration from the iliac crests under general or regional anesthesia.  The marrow is then preserved and re-infused following completion of a potent chemotherapy regimen.  This process provides pluripotent marrow stem cells to reconstitute (i.e., rescue) the patient's marrow from the myeloablative effects of high dose cytotoxic chemotherapeutic agents.

Allogeneic bone marrow transplant refers to the use of functional hematopoietic stem cells from a healthy donor to restore bone marrow function following HDC.  For patients with marrow-based malignancies, the use of allogeneic stem cells offers the advantage of lack of tumor cell contamination.  Furthermore, allogeneic stem cells may be associated with a beneficial graft versus tumor effect.

Tandem (sequential) transplant protocols utilize a cycle of HDC with ASCT followed in approximately 6 months by a second cycle of HDC and/or TBI with another ASCT.  This is done in an attempt to obtain greater and extended response rates.  To date, there have been no definitive studies showing that tandem transplants improve response rates, event-free survival (EFS) or overall survival (OS) more than single transplants for patients with HD.  Therefore, tandem transplant protocols are considered experimental and investigational.

In a clinical trial, Papadoupoulos and coleagues (2005) assessed the effectiveness of a novel regimen of tandem HDC (THDC) with autologous stem cell transplantation in the treatment of patients with poor risk lymphoma.  A total of 41 patients (median age of 40 years, range of 15 to 68 years) with poor risk non-Hodgkin's lymphoma and HD were enrolled.  Tandem HDC consisted of melphalan (180 mg/m2) and escalating dose mitoxantrone (30 to 50 mg/m2) (MMt) for the 1st conditioning regimen, and thiotepa (500 mg/m2), carboplatin (800 mg/m2), and escalating dose etoposide phosphate (400 to 850 mg/m2), (ETCb) as the 2nd regimen.  In all, 31 patients (76 %) completed both transplants, with a median time between transplants of 55 days (range of 26 to 120 days).  The maximum tolerated dose was determined as 40 mg/m2 for mitoxantrone and 550 mg/m2 for etoposide phosphate.  The overall toxic death rate was 12 %.  Following HDC, 10 of 24 evaluable patients (42 %) were in complete remission.  The 2-year OS and EFS is 67 % (95 % confidence interval (CI): 52 % to 81 %) and 45 %, (95 % CI: 29 % to 61 %) for the 41 patients enrolled; and 69 % (95 % CI: 525 % to 586 %) and 48 % (95 % CI: 30 % to 67 %) for the 31 patients completing both transplants.  This THDC regimen is feasible but with notable toxicity in heavily pre-treated patients; its role in the current treatment of high-risk lymphoma remains to be determined.

Prior to HDC-ABMT, patients generally undergo induction therapy with vincristine, doxorubicin and dexamethasone, melphalan and prednisone or other combination salvage regimens.  Conventional dosages of these drugs can typically be given on an outpatient basis.  Hospitalization may be required due to neutropenic fever, nausea and vomiting, mucositis, diarrhea, or inadequate oral intake.  Standard severity of illness/intensity of service criteria should be applied to these admissions.

Prior to peripheral stem cell collection, an apheresis catheter may be inserted during an ambulatory surgical procedure.  The apheresis catheter can be placed during the same anesthesia procedure if a bone marrow harvest is also planned.  Apheresis is usually performed daily on an outpatient basis until adequate stem cells are collected.  Typically, from 5 to 10 procedures are necessary.

Stem cell mobilization, in which cyclophosphamide and/or GM-CSF are used to flush the critical stem cells from the bone marrow into the peripheral circulation, may also be part of the stem cell collection.  Protocols vary -- some institutions administer intermediate doses of cyclophosphamide (4 g/m2) as an outpatient procedure, followed by apheresis in 5 to 14 days when the blood counts have recovered.  When high dose cyclophosphamide (6 g/m2) is used, a hospitalization of about 4 days is required for pre- and post-chemotherapy hydration.  After completion of the cyclophosphamide regimen, the patient can usually be discharged; apheresis can be administered on an outpatient basis once the acute period of bone marrow hypoplasia has resolved.

Hospitalization for the HDC component of the procedure depends on the regimen.  High-dose melphalan (140 to 200 mg/m2) can usually be given as an outpatient with home hydration therapy.  This outpatient HDC is the exception.  Other high-dose combination therapies, such as EDAP (etoposide, dexamethasone, ara-C and cisplatin) usually require hospitalization due to nausea and vomiting, mucositis, diarrhea and inadequate oral intake.  Any regimen that includes TBI is likely to require a prolonged hospital stay, usually averaging about 30 days.  Patients receiving HDC with or without TBI are usually initially treated in a private room for about 1 week until the blood counts start to drop.  Then, patients are typically transferred to a specialized laminar flow room for the duration of their hospital stay.

Usual length of stay for patients undergoing peripheral stem cell collection with high- dose cyclophosphamide mobilization is 4 days.  Other stem cell mobilization protocols normally do not require a hospital stay.

Usual length of stay for patients hospitalized for complications related to HDC depend on resolution of fever (i.e., fever-free for 48 hours while off all antibiotics), maintenance of adequate blood counts (i.e., WBC greater than 500), and resolution of other morbidities such as mucositis and diarrhea.  The patient must also be able to maintain adequate oral intake.  Hospital stays usually range from 2 to 4 weeks.  Patients may be discharged even if an adequate platelet count is transfusion dependent; platelet transfusions can be given on an outpatient basis.

Usual length of stay for patients undergoing HDC in conjunction with TBI is 30 days.  Discharge parameters are similar to above: fever-free for 48 hours, adequate blood counts (WBC greater than 1,000).  Patients may be discharged even if an adequate platelet count if transfusion dependent; platelet transfusions can be given on an outpatient basis.

Studies on Autologous Transplant

Gribben and colleagues (1989) reported the findings of a non-randomized study in which a high-dose combination chemotherapy regimen was followed by autologous bone marrow rescue (ABMR).  The study was comprised of 44 patients with active HD who were resistant to standard regimen therapy.  Previous treatments of the patients involved in the study were reported as follows: 2 patients had received front-line, alternating chemotherapy and failed to respond; they progressed to ABMR.  The remainder of the patients had received at least 2 regimens of chemotherapy.  In addition, 28 patients had also received radiotherapy.  Of these 44 patients, 22 had never achieved a complete remission (CR), while the other 22 had achieved a CR in response to first-line therapy but relapsed.  After the use of HDC and ABMR the following results were described -- 23 patients achieved a partial response (PR); 2 patients (initially classified as having a PR) who presented with a residual mediastinal mass at 3 months had slow resolution of the mass, and were classified as having a CR 6 months after ABMR; 4 patients had demonstrated a progressive decrease in the size of a residual mediastinal mass over 10 to 33 months without receiving further treatment; 7 patients (initially classified as having a PR) underwent post-ABMR radiotherapy to sites of residual disease, and 5 of these patients subsequently achieved a CR; 4 patients did not respond to HDC and ABMR, 3 of whom died within 6 months of the procedure; and 2 patients died of complications related to sepsis.  In summary, 22 patients (50 %) achieved a CR 6 months after ABMR, and 4 other patients were free of disease progression.  Two patients relapsed from CR at 7 and 9 months following ABMR; they subsequently died from progressive disease.  According to the authors, the remaining 20 patients who achieved a CR remain in remission.  They concluded that the use of HDC followed by ABMR appears to be an efficacious salvage regimen for patients with refractory HD.

Chopra and associates (1993) reported the results of 155 patients with relapsed or resistant HD who were treated with HDC followed by ABMR.  At the time of transplant, 46 patients were primarily refractory to induction therapy, 7 were good partial responders, and 52 were in first relapse, 37 in second relapse, and 13 in third relapse.  At 3 months 43 (28 %) patients were assessed as complete responders.  Seventy-two (46 %) patients were assessed to have partial responses (PR).  Twenty-four patients (16 %) showed no response or progression.  At 6 months, 53 patients were assessed as complete responders.  Thirteen patients in PR at 3 months had achieved a CR by 6 months, this occurring in 8 patients after radiotherapy to residual masses, and 5 patients without any further treatment indicative of slow resolution of their tumor masses.  Fifty-one patients still had non-progressive disease with persistent CT abnormalities, 26 patients had relapsed with progressive disease, and 8 patients had died of progressive HD.  Overall, 104 of 155 (67 %) had a good response to ABMR.  By 6 months, there were 17 procedure-related deaths.  The actuarial OS at 5 years was 55 %, with a progression-free survival (PFS) of 50 %.  The authors found that patients undergoing ABMR in second and third relapse were faring significantly better than patients in first relapse and primary refractory disease.

Bierman and co-workers (1993) examined the influence of pre-transplant prognostic factors and evaluated long-term follow-up in a group of 128 patients with HD.  All patients in the study were refractory to primary therapy, or had relapsed after attaining a remission, and underwent HDC followed by ABMR.  Following transplantation, 57 (45 %) patients achieved CR; 9 (7 %) patients who were transplanted without evidence of disease continued in remission following the transplant.  Seven (5 %) patients received localized radiation following transplantation to areas of apparent residual disease, and they converted to CR.  In total, 73 (57 %) patients were in CR following transplantation, 23 (18 %) patients achieved a PR, and 21 (16 %) had no response.  There were 11 (9 %) early deaths.  Among the 73 patients in CR following transplantation, 34 have subsequently died; including 6 who died without evidence of disease between 6 and 59 months following transplantation.  At the time of the report, 43 patients were alive, including 28 who remain free from progression.  The median survival time for the entire patient group is 31.5 months, and the median failure-free survival time is 7.3 months.  The estimated 4-year OS is 45 % and the 4-year failure-free survival is estimated as 25 %.  The authors concluded that superior results were seen in patients without extensive prior chemotherapy and in those with a good performance status.

In a review, Mink and Armitage (2001) stated that ASCT has proven to be beneficial in selected patients with HD.  Transplantation appeared to increase EFS in patients who failed to enter complete remission with initial therapy.  When a patient relapses after a complete remission, transplantation is probably the best option and particularly so if the remission lasted less than 1 year.  Transplantation as part of primary therapy for very high-risk patients may be beneficial, but is not standard therapy at this time.  Lazarus et al (2001) reviewed data from the Autologous Blood and Marrow Transplant Registry (n = 414) to determine relapse, disease-free survival, OS, and prognostic factors in patients with relapsed HD.  They concluded that autologous hematopoietic stem cell transplantation (autotransplantation) should be considered for patients with HD in first relapse or second remission.

Studies on Allogeneic Transplant

Lundberg and associates (1991) performed a non-randomized, prospective study to ascertain whether HDC followed by allogeneic bone marrow transplantation is an effective treatment in relapsed or refractory lymphoma.  The study group consisted of 22 patients with relapsed or refractory lymphoma.  Seven patients had HD; the remaining 15 patients had non-Hodgkin's lymphoma (NHL).  The median age was 30 years.  The treatment regimen consisted of the following: cytarabine, cytoxan, TBI, and methylprednisolone.  Seven patients with significant bulky disease received localized radiotherapy prior to the preparative regimen.  Total body irradiation was begun 48 hours after the last dose of chemotherapy.  Patients who had undergone radiotherapy treatments were precluded from the use of standard TBI-based regimens; thus, only myeloablative chemotherapy was used in those patients.  Patients who were treated with TBI received graft-versus-host-disease prophylaxis with T-cell depletion and cyclosporine.  The authors recounted the following results in the 7 patients with HD: 4 patients were alive; 3 in CR (19 to 43 months post-transplant) and 1 with recurrent lymphoma.  The remaining 3 patients died due to the following complications;
  1. aspergillus,
  2. hepatic veno-occlusive-disease, and
  3. recurrent lymphoma. 
The authors concluded that, allogeneic bone marrow transplantation appeared superior to salvage chemotherapy for the achievement of long-term, lymphoma-free survival and may be preferable to autologous bone marrow transplantation for selected patients.
Anderson and colleagues (1993) carried out a non-randomized, prospective study on 127 patients undergoing myeloablative therapy for relapsed or refractory HD.  The purpose of the study was to determine efficacy of transplant (autologous or allogeneic) post-failure of MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) - and ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine)-like regimens.  The study group consisted of the following:
  1. 23 patients with primary refractory disease,
  2. 34 in early first relapse or second CR, and
  3. 70 with refractory first relapse or disease beyond second CR. 
The median age was 29.  Disease stage at diagnosis was I to IV.  A total of 68 patients received autologous marrow, 6 syngeneic marrow, and 53 allogeneic marrow.  The preparative regimen in 94 of the 127 patients consisted of cytoxan and TBI, or cytoxan, carmustine (BCNU) and etoposide.  The remaining patients received busulfan and cytoxan or other regimens.  Twelve of the 53 patients who received an allogeneic transplant have survived for a median of 1,661 days, all free of relapse (20 % actuarial survival and 22 % actuarial EFS at 5 years).  Twenty-four of 68 patients who underwent an autologous transplant were alive (median survival time of 758 days; 5-year actuarial survival, 13 %), 14 of whom survived without evidence of relapse (median survival time of 740 days; 5-year actuarial EFS, 14 %).  The authors determined that the EFS rate did not differ statistically when comparing allogeneic to autologous transplants.  However, there was a trend toward decreased relapse rates in the allogeneic recipients.  The authors state that, although autologous bone marrow transplantation is often preferred over allogeneic transplantation in HD because of perceived lower mortality, few studies have had sufficient numbers of patients to study the effect of marrow source on outcome.  Moreover, their results demonstrated a lower relapse rate for HLA-identical compared with autologous marrow recipients, despite more frequent poor prognostic features among the allogeneic group.  The authors concluded that, the use of HLA-identical marrow should be considered in patients who have features that suggest a higher risk for relapse, such as the presence of bulky disease and history of a short first CR, and who also have features that suggest a lower risk of non-relapse mortality.
Mendoza and co-workers (1995) studied 23 patients with relapsed or resistant aggressive lymphoma.  The purpose of this study was to determine if HDC followed by allogeneic bone marrow transplant is an effective means of treatment for relapsed or aggressive Hodgkin's or NHL.  The study group consisted of 23 patients -- 9 patients with stage III or IV HD and 14 patients with NHL.  In the HD group, patients were accepted for transplant if they met the following criteria:
    1. failure to attain a CR despite prior chemotherapy (with MOPP or ABVD),
    2. tumor progression despite chemotherapy, or
    3. relapse within 1 year of achieving remission with the MOPP and/or ABVD regimen.  Patients were under age 50. 
The following treatment protocols were used: TBI combined with cytoxan; TBI, cytoxan and vinblastine; TBI, cytoxan and etoposide; and busulfan and cytoxan.  The authors recounted the following results: 4 of the 9 patients with HD were alive and disease-free at 1.3 to 94.8 months post-transplant.  There was significant toxicity associated with the treatment such as infection, hepatotoxicity, interstitial pneumonitis, hemorrhage, and graft-versus-host disease (GVHD).  However, the authors stated that allogeneic bone marrow transplantation is an effective salvage treatment for relapsed or refractory lymphoma.

Laurence and Goldstone (1999) stated that there is an increasing tendency to consider allogeneic transplantation in HD.  There may be some limited graft-versus-Hodgkin's lymphoma effect, but this is outweighed by the greatly increased treatment toxicity associated with the allogeneic procedure.  It is possible, however, that modern low-intensity conditioning regimens, the so-called mini-allograft approach, may increase the use of allogeneic transplantation for poor-prognosis Hodgkin's lymphoma patients in the future.

In a recent review, Hale and Phillips (2000) stated that some poor-prognosis patients with HD and NHL, usually with recurrent and/or refractory disease, are rarely curable with standard chemoradiotherapy.  Autologous hematopoietic stem cell transplantation has been reported to improve long-term disease-free survival in some of these patients.  Unfortunately, a number of patients are unsuitable for autologous transplantation as a consequence of damaged stem cell pool involvement or other disease processes of the marrow.  These individuals may benefit from allogeneic stem cell transplantation.  In addition to the therapeutic effect of HDC with or without TBI, an immunologic [namely, graft-versus-lymphoma (GVLym)] effect may be present in some patients undergoing allogeneic transplantation, resulting in a lower relapse rate than autotransplants.  However, allografts are often associated with a higher non-relapse mortality due primarily to GVHD; unfortunately, GVHD and GVLym are difficult to differentiate.  As a result, full exploitation of this GVLym effect may necessitate the modification of commonly employed conditioning regimens.  If successful, these modifications may lead to an additional reduction relapse rate without additional morbidity.  Furthermore, when combined with low-intensity conditioning, such modifications may allow patients who otherwise would not be candidates for standard transplant regimens to be allografted.

Guidelines from Cancer Care Ontario (2009) recommend autologous stem cell transplantation as a treatment option for eligible chemosensitive patients with Hodgkin's lymphoma who are refractory to or who have relapsed after primary chemotherapy. These guidelines state that allogeneic stem cell transplantation is an option for chemosensitive patients with refractory or relapsed Hodgkin's lymphoma who are not candidates for autologous stem cell transplantation or who have a syngeneic (identical twin) donor. The guidelines do not recommend stem cell transplantation as part of primary therapy for Hodgkin's lymphoma.

Messer et al (2014) stated that allogeneic stem cell transplant (allo-SCT) is considered a clinical option for patients with Hodgkin lymphoma (HL) who have experienced at least 2 chemo-sensitive relapses.  These investigators determined the benefits and harms of allo-SCT with an unrelated donor (UD) versus related donor (RD) allo-SCT for adult patients with HL.  Alternative donor sources such as haplo-identical donor cells (Haplo) and umbilical cord blood (UCB) were also included.  The available evidence was limited.  A total of 10 studies were included in this assessment; 4 studies provided sufficient data to compare UD with RD allo-SCT.  None of these studies was a randomized controlled trial (RCT).  Additionally, 3 non-comparative studies, such as registry analyses, which considered patients with UD transplants were included.  The risk of bias in the studies was high.  Results on overall and PFS showed no consistent tendency in favor of a donor type.  Results on therapy-associated mortality and acute (grade II to IV) and chronic GVHD were also inconsistent.  The study comparing UCB with RD transplants and 2 non-comparative studies with UCB transplants showed similar results.  One of the studies comparing additionally Haplo with RD transplants indicated a benefit in PFS for the Haplo transplant group.  The authors concluded that these findings did not indicate a substantial outcome disadvantage of UD and alternative donor sources versus RD allo-SCT for adult patients with advanced HL.

Gauthier and associates (2017) stated that allo-SCT following a non-myeloablative (NMA) or reduced-intensity conditioning (RIC) is considered a valid approach to treat patients with refractory/relapsed HL.  When an HLA-matched donor is lacking a graft from a familial haploidentical (HAPLO) donor, a mis-matched unrelated donor (MMUD) or CB might be considered.  In this retrospective study, these investigators compared the outcome of patients with HL undergoing a RIC or NMA allo-SCT from HAPLO, MMUD or CB.  A total of 98 patients were included.  Median follow-up was 31 months for the whole cohort.  All patients in the HAPLO group (n = 34) received a T-cell replete allo-SCT after a NMA (FLU-CY-TBI, n = 31, 91 %) or a RIC (n = 3, 9 %) followed by post-transplant cyclophosphamide (PT-Cy).  After adjustment for significant co-variates, MMUD and CB were associated with significantly lower GVHD-free relapse-free survival (GRFS; hazard ratio (HR) = 2.02, p = 0.03 and HR = 2.43, p = 0.009, respectively) compared with HAPLO donors.  The authors concluded that higher GRFS was observed in HL patients receiving a RIC or NMA allo-SCT with PT-Cy from HAPLO donors.  They stated that these findings suggested they should be favored over MMUD and CB in this setting.

Mei and Chen (2018) noted that HL is a highly curable B-cell lymphoma, and approximately 90 % of patients who present with early-stage (stage I to II) disease and 70 % of patients who present with late-stage disease will be cured with standard front-line treatment.  For patients with relapsed or refractory (r/r) disease after initial therapy, the standard of care is salvage chemotherapy, followed by autologous SCT (auto-SCT).  Although this approach will cure a significant proportion of patients, up to 50 % of patients will experience disease progression after auto-SCT, and this population has historically had a very poor prognosis.  In the past, further salvage chemotherapy, followed by allo-SCT, has been the only option associated with a significant probability of long-term survival, owing to a graft-versus-lymphoma effect.  However, this approach has been complicated by high rates of treatment-related morbidity and mortality and a high risk of disease relapse.  Furthermore, many patients have been unable to proceed to allo-SCT because of disease refractoriness, poor performance status, or the lack of a donor.  However, significant therapeutic advances in recent years have greatly expanded the options for patients with post-auto-SCT r/r HL.  These include the anti-CD30 antibody-drug conjugate brentuximab vedotin and the check-point inhibitors nivolumab and pembrolizumab, as well as increasing experience with alternative donor allo-SCT, especially from HAPLO donors.

Haploidentical Versus HLA-Matched Related Donors in Allogeneic Hematopoietic Cell Transplantation

Gauthier and colleagues (2018) noted that the question of the best donor type between HAPLO and matched-related donors (MRD) for patients with advanced HL receiving an allo hematopoietic cell transplantation (allo-HCT) is still debated.  Given the lack of data comparing these 2 types of donor in the setting of NMA or RIC allo-HCT, these researchers performed a multi-center, retrospective study using GRFS as the primary end-point.  They analyzed the data of 151 consecutive HL patients who underwent NMA or RIC allo-HCT from a HAPLO (n  =  61) or MRD (n  =  90) between January 2011 and January 2016.  GRFS was defined as the probability of being alive without evidence of relapse, grade 3 to 4 acute GVHD or chronic GVHD.  In multi-variable analysis, MRD donors were independently associated with lower GRFS compared to HAPLO donors (HR = 2.95, p < 0.001).  Disease status at transplant other than complete remission was also associated with lower GRFS in multi-variable analysis (HR = 1.74, p = 0.01).  In addition, the administration of anti-thymocyte globulin was independently linked to higher GRFS (HR = 0.52, p = 0.009).  The authors concluded that they observed significantly higher GRFS in HL patients receiving an allo-HCT using the HAPLO PT-Cy platform compared to MRD.

Tandem Autologous Hematopoietic Cell Transplantation

Based on promising pilot data, Smith and co-workers (2017) carried out a phase-II clinical trial on the use of tandem autologous hematopoietic stem cell transplant (AHSCT) for the treatment of relapsed/refractory HL to determine if long-term PFS could be improved.  Patients were enrolled after salvage therapy and stem cell collection.  Sensitivity to salvage was defined by 1999 Standardized Response Criteria and did not include 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET).  Cycle 1 consisted of melphalan 150 mg/m2 with 50 % of the stem cells.  For stable disease (SD) or better, patients received cycle 2 consisting of single doses of etoposide 60 mg/kg and cyclophosphamide 100 mg/kg and either TBI 12 Gy in 8 fractions over 4 days or BCNU 150 mg/m2/day for 3 days with the remaining stem cells.  Of 98 enrolled patients, 89 were eligible and treated: 82 completed both cycles of AHSCT, 47 (53 %) had primary refractory HL, and 72 (81 %) were resistant to salvage therapy.  There were no treatment-related deaths (TRDs) in the 1st year after AHSCT.  With a median follow-up of 6.2 years (range of 2 to 7.7) for eligible patients who remained alive, the 2-year and 5-year PFS were 63 % (95 % CI: 52 % to 72 %) and 55 % (95 % CI: 44 % to 64 %) respectively; the 2-year and 5-year OS were 91 % (95 % CI: 83 % to 95 %) and 84 % (95 % CI: 74 % to 90 %), respectively.  Univariate Cox regression analysis showed Zubrod performance status and lactate dehydrogenase levels greater than 1 times upper limit of normal at the time of enrollment were significantly associated with PFS.  The authors concluded that the observed 5-year PFS of 55 % suggested that the tandem approach appeared to be effective in treating HL patients demonstrated to have poor prognosis in prior single AHSCT trials.  These findings need to be further investigated.

Combined Haploidentical and Umbilical Cord Blood Allogeneic Stem Cell Transplantation for High-Risk Lymphoma

Hsu and colleagues (2018) stated that limited studies have reported on outcomes for lymphoid malignancy patients receiving alternative donor allogeneic stem cell transplants.  These researchers have previously described combining CD34-selected haploidentical grafts with UCB (haplo-cord) to accelerate neutrophil and platelet engraftment.  These investigators examined the outcome of patients with lymphoid malignancies undergoing haplo-cord transplantation.  They analyzed 42 lymphoma and chronic lymphoblastic leukemia (CLL) patients who underwent haplo-cord allo-SCT.  Patients underwent transplant for HL (n = 9, 21 %), CLL (n = 5, 12 %) and NHL (n = 28, 67 %), including 13 T cell lymphomas; 24 patients (52 %) had 3 or more lines of therapies; 6 (14 %) and 1 (2 %) patients had prior auto- and allo-SCT, respectively.  At the time of transplant, 12 patients (29 %) were in CR, 18 had chemotherapy-sensitive disease, and 12 patients had chemotherapy-resistant disease; 7 (17 %), 11 (26 %), and 24 (57 %) patients had low, intermediate, and high disease risk index before transplant.  Co-morbidity index was evenly distributed among 3 groups, with 13 (31 %), 14 (33 %), and 15 (36 %) patients scoring 0, 1 to 2, and greater than or equal to 3.  Median age for the cohort was 49 years (range of 23 to 71).  All patients received fludarabine/melphalan/anti-thymocyte globulin conditioning regimen and post-transplant GVHD prophylaxis with tacrolimus and mycophenolate mofetil.  The median time to neutrophil engraftment was 11 days (range of 9 to 60) and to platelet engraftment 19.5 days (range of 11 to 88).  Cumulative incidence of non-relapse mortality was 11.6 % at 100 days and 19 % at 1 year.  Cumulative incidence of relapse was 9.3 % at 100 days and 19 % at 1 year.  With a median follow-up of survivors of 42 months, the 3-year rates of GVHD relapse free survival (RFS), PFS, and OS were 53 %, 62 %, and 65 %, respectively, for these patients.  Only 8 % of the survivors had chronic GVHD.  The authors concluded that haplo-cord transplantation offered a transplant alternative for patients with recurrent or refractory lymphoid malignancies who lack matching donors.  Both neutrophil and platelet count recovery was rapid, non-relapse mortality was limited, excellent disease control could be achieved, and the incidence of chronic GVHD was limited.  Thus, haplo-cord achieved high rates of engraftment and encouraging results.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:
38204 Management of recipient hematopoietic progenitor cell donor search and cell acquisition
38205 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogenic
38206     autologous
38210 Transplant preparation of hematopoietic progenitor cells; specific cell depletion with harvest, T-cell depletion
38211     tumor cell depletion
38212     red blood cell removal
38213     platelet depletion
38230 Bone marrow harvesting for transplantation
38232      autologous
38240 Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241     autologous transplantation
86813 HLA typing; A, B or C multiple antigens
86817     DR/DQ, multiple antigens
86821     lymphocyte culture, mixed (MCL)
86822     lymphocyte culture, primed (PLC)

Other CPT codes related to the CPB:
77261 - 77295 Radiation therapy
96401 - 96450 Chemotherapy administration code range

HCPCS code covered if selection criteria are met:
S2150 Bone marrow or blood-derived peripheral stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition

Other HCPCS codes related to the CPB:
J9000 - J9999 Chemotherapy drugs code range
Q0083 - Q0085 Chemotherapy administration

ICD-10 codes covered if selection criteria are met:
C81.00 - C81.99 Hodgkin lymphoma

The above policy is based on the following references:

  1. Gribben JG, Linch, DC, Singer CRJ, et al. Successful treatment of refractory Hodgkin's disease by high dose combination chemotherapy and autologous bone marrow transplantation. Blood. 1989;73:34-44.
  2. Jones RJ, Piantadosi S, Mann RB, et al. High dose cytotoxic therapy and bone marrow transplantation for relapsed Hodgkin's disease. J Clin Oncol. 1990;8:527-537.
  3. Lundberg JH, Hansen RM, Chitambar CR, et al. Allogeneic bone marrow transplantation for relapsed and refractory lymphoma using genotypically HLA-identical and alternative donors. J Clin Oncol. 1991;9(10):1848-1859.
  4. Bierman PJ, Bagin RG, Jagannath S, et al. High dose chemotherapy followed by autologous hematopoietic rescue in Hodgkin's disease: Long term follow up in 128 patients. Ann Oncol. 1993:4:767-773.
  5. Yahalom J, Gulati SC, Toia M, et al. Accelerated hyperfractionated total-lymphoid irradiation, high-dose chemotherapy and autologous bone marrow transplantation for refractory and relapsing patients with Hodgkin's disease. J Clin Oncol. 1993;11:1062-1070.
  6. Linch DC, Winfield D, Goldstone AH, et al. Dose intensification with autologous bone marrow transplantation in relapsed and resistant Hodgkin's disease: Results of a BNLI randomized trial. Lancet. 1993;341:1051-1054.
  7. Chopra R, McMillan AK, Linch DC, et al. The place of high dose BEAM therapy and autologous bone marrow transplantation in poor risk Hodgkin's disease. A single center eight year study of 155 patients. Blood. 1993;81:1137-1145.
  8. Anderson JE, Litzow MR, Appelbaum FR, et al. Allogeneic, syngeneic, and autologous marrow transplantation for Hodgkin's disease: The 21-year Seattle experience. J Clin Oncol. 1993;11(12):2342-2350.
  9. Franco T, Gould DA. Allogeneic bone marrow transplantation. Semin Oncol Nurs. 1994;10(1):3-11.
  10. Reece DE, Barnett MJ, Shepherd JD, et al. High-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV +/- P) and autologous transplantation for patients with Hodgkin's disease who fail to enter a complete remission after combination chemotherapy. Blood. 1995;86(2):451-456.
  11. Demirer T, Weaver CH, Buckner CD, et al. High-dose cyclophosphamide, carmustine, and etoposide followed by allogeneic bone marrow transplantation in patients with lymphoid malignancies who had received prior dose-limiting radiation therapy. J Clin Oncol. 1995;13(3):596-602.
  12. Mendoza E, Territo M, Schiller G, et al. Allogeneic bone marrow transplantation for Hodgkin's and non-Hodgkin's lymphoma. Bone Marrow Transplant. 1995;15(2):299-303.
  13. Brice P, Bouabdallah R, Moreau P, et al. Prognostic factors for survival after high-dose therapy and autologous stem cell transplantation for patients with relapsing Hodgkin's disease: Analysis of 280 patients from the French registry. Societe Francaise de Greffe de Moelle. Bone Marrow Transplant. 1997;20(1):21-26.
  14. Yuen AR, Rosenberg SA, Hoppe RT, et al. Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin's disease. Blood. 1997;89(3):814-822.
  15. Horning SJ, Chao NJ, Negrin RS, et al. High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: Analysis of the Stanford University results and prognostic indices. Blood. 1997;89(3):801-813.
  16. Dann EJ, Daugherty CK, Larson RA. Allogeneic bone marrow transplantation for relapsed and refractory Hodgkin's disease and non-Hodgkin's lymphoma. Bone Marrow Transplant. 1997;20(5):369-374.
  17. Moreau P, Fleury J, Brice P, et al. Early intensive therapy with autologous stem cell transplantation in advanced Hodgkin's disease: Retrospective analysis of 158 cases from the French registry. Bone Marrow Transplant. 1998;21(8):787-793.
  18. Laurence AD, Goldstone AH. High-dose therapy with hematopoietic transplantation for Hodgkin's lymphoma. Semin Hematol. 1999;36(3):303-312.
  19. Hale GA, Phillips GL. Allogeneic stem cell transplantation for the non-Hodgkin's lymphomas and Hodgkin's disease. Cancer Treat Rev. 2000;26(6):411-427.
  20. Simnett SJ, Stewart LA, Sweetenham J, et al. Autologous stem cell transplantation for malignancy: A systematic review of the literature. Clin Lab Haematol. 2000;22(2):61-72
  21. Mink SA, Armitage JO. High-dose therapy in lymphomas: A review of the current status of allogeneic and autologous stem cell transplantation in Hodgkin's disease and non-Hodgkin's lymphoma. Oncologist. 2001;6(3):247-256.
  22. Lazarus HM, Loberiza FR Jr, Zhang MJ, et al. Autotransplants for Hodgkin's disease in first relapse or second remission: A report from the autologous blood and marrow transplant registry (ABMTR). Bone Marrow Transplant. 2001;27(4):387-396.
  23. Reece DE. Hematopoietic stem cell transplantation in Hodgkin disease. Curr Opin Oncol. 2002;14(2):165-170.
  24. Carella AM, Cavaliere M, Lerma E, et al. Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin's disease and non-Hodgkin's lymphoma. J Clin Oncol. 2000;18(23):3918-3924.
  25. Federico M, Bellei M, Brice P, et al, EBMT/GISL/ANZLG/SFGM/GELA Intergroup HD01 Trial. High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy. J Clin Oncol. 2003;21(12):2320-2325.
  26. Schmitz N, Sureda A, Robinson S. Allogeneic transplantation of hematopoietic stem cells after nonmyeloablative conditioning for Hodgkin's disease: Indications and results. Semin Oncol. 2004;31(1):27-32.
  27. Ahmed T, Rashid K, Waheed F, et al. Long-term survival of patients with resistant lymphoma treated with tandem stem cell transplant. Leuk Lymphoma. 2005;46(3):405-414.
  28. Papadopoulos KP, Noguera-Irizarry W, Wiebe L, et al. Pilot study of tandem high-dose chemotherapy and autologous stem cell transplantation with a novel combination of regimens in patients with poor risk lymphoma. Bone Marrow Transplant. 2005;36(6):491-497.
  29. Seftel M, Rubinger M. The role of hematopoietic stem cell transplantation in advanced Hodgkin Lymphoma. Transfus Apher Sci. 2007;37(1):49-56.
  30. Sureda A, Robinson S, Canals C, et al. Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma: An analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2008;26(3):455-462.
  31. Anderlini P, Saliba R, Acholonu S, et al. Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin's lymphoma: The updated M.D. Anderson Cancer Center experience. Haematologica. 2008;93(2):257-264.
  32. Morschhauser F, Brice P, Fermé C, et al; GELA/SFGM Study Group. Risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation for first relapse/refractory Hodgkin's lymphoma: Results of the prospective multicenter H96 trial by the GELA/SFGM study group. J Clin Oncol. 2008;26(36):5980-5987.
  33. Devetten MP, Hari PN, Carreras J, et al. Unrelated donor reduced-intensity allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2009;15(1):109-117.
  34. Robinson SP, Sureda A, Canals C, et al; Lymphoma Working Party of the EBMT. Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin's lymphoma: Identification of prognostic factors predicting outcome. Haematologica. 2009;94(2):230-238.
  35. Freytes CO, Lazarus HM. Second hematopoietic SCT for lymphoma patients who relapse after autotransplantation: Another autograft or switch to allograft? Bone Marrow Transplant. 2009;44(9):559-569.
  36. Brusamolino E, Bacigalupo A, Barosi G, et al. Classical Hodgkin's lymphoma in adults: Guidelines of the Italian Society of Hematology, the Italian Society of Experimental Hematology, and the Italian Group for Bone Marrow Transplantation on initial work-up, management, and follow-up. Haematologica. 2009;94(4):550-565.
  37. Imrie K, Rumble RB, Crump M; Advisory Panel on Bone Marrow and Stem Cell Transplantation, and the Hematology Disease Site Group of Cancer Care Ontario’s Program in Evidence-based Care. Cancer Care Ontario. Stem cell transplantation in adults. Recommendation Report 1. Toronto, ON: Cancer Care Ontario; January 30, 2009.
  38. Freed J, Kelly KM. Current approaches to the management of pediatric Hodgkin lymphoma. Paediatr Drugs. 2010;12(2):85-98.
  39. IQWiG. Unrelated donor allogeneic stem cell transplantation for Hodgkin's lymphoma. Summary. A09-04. Cologne, Germany: Institut fuer Qualitaet und Wirtschaftlichkeit im Gesundheitswesen (IQWiG); 2010.
  40. Daw S, Wynn R, Wallace H. Management of relapsed and refractory classical Hodgkin lymphoma in children and adolescents. Br J Haematol. 2011;152(3):249-260.
  41. Corradini P, Sarina B, Farina L. Allogeneic transplantation for Hodgkin's lymphoma. Br J Haematol. 2011;152(3):261-272.
  42. Rancea M, Monsef I, von Tresckow B, et al. High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. Cochrane Database Syst Rev. 2013;6:CD009411.
  43. Harker-Murray PD, Drachtman RA, Hodgson DC, et al. Stratification of treatment intensity in relapsed pediatric Hodgkin lymphoma. Pediatr Blood Cancer. 2014;61(4):579-586.
  44. Messer M, Steinzen A, Vervolgyi E, et al. Unrelated and alternative donor allogeneic stem cell transplant in patients with relapsed or refractory Hodgkin lymphoma: A systematic review. Leuk Lymphoma. 2014;55(2):296-306.
  45. Rashidi A, Ebadi M, Cashen AF. Allogeneic hematopoietic stem cell transplantation in Hodgkin lymphoma: A systematic review and meta-analysis. Bone Marrow Transplant. 2016;51(4):521-528.
  46. Martino M, Festuccia M, Fedele R, et al. Salvage treatment for relapsed/refractory Hodgkin lymphoma: Role of allografting, brentuximab vedotin and newer agents. Expert Opin Biol Ther. 2016;16(3):347-364.
  47. von Tresckow B, Moskowitz CH. Treatment of relapsed and refractory Hodgkin lymphoma. Semin Hematol. 2016;53(3):180-185.
  48. Gauthier J, Castagna L, Garnier F, et al. Reduced-intensity and non-myeloablative allogeneic stem cell transplantation from alternative HLA-mismatched donors for Hodgkin lymphoma: A study by the French Society of Bone Marrow Transplantation and Cellular Therapy. Bone Marrow Transplant. 2017;52(5):689-696.
  49. Smith EP, Li H, Friedberg JW, et al. Tandem autologous hematopoietic cell transplantation for patients with primary progressive or recurrent Hodgkin lymphoma: A SWOG and Blood and Marrow Transplant Clinical Trials Network Phase II Trial (SWOG S0410/BMT CTN 0703). Biol Blood Marrow Transplant. 2017 Dec 28 [Epub ahead of print].
  50. Mei M, Chen R. How to approach a Hodgkin lymphoma patient with relapse after autologous SCT: Allogeneic SCT. Clin Lymphoma Myeloma Leuk. 2018;18(1):26-33.
  51. Kallam A, Armitage JO. Current and emerging treatment options for a patient with a second relapse of Hodgkin's lymphoma. Expert Rev Hematol. 2018;11(4):293-300.
  52. Karantanos T, Politikos I, Boussiotis VA. Advances in the pathophysiology and treatment of relapsed/refractory Hodgkin's lymphoma with an emphasis on targeted therapies and transplantation strategies. Blood Lymphat Cancer. 2017;7:37-52.
  53. Hsu J, Artz A, Mayer SA, et al. Combined haploidentical and umbilical cord blood allogeneic stem cell transplantation for high-risk lymphoma and chronic lymphoblastic leukemia. Biol Blood Marrow Transplant. 2018;24(2):359-365.
  54. Gauthier J, Poiré X, Gac AC, et al. Better outcome with haploidentical over HLA-matched related donors in patients with Hodgkin's lymphoma undergoing allogeneic haematopoietic cell transplantation-a study by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy. Bone Marrow Transplant. 2018 Jan 12 [Epub ahead of print].
  55. Mottok A, Steidl C. Biology of classical Hodgkin lymphoma: Implications for prognosis and novel therapies. Blood. 2018 Mar 2 [Epub ahead of print].